Physical mechanism and modeling of heat generation and transfer in magnetic fluid hyperthermia through Néelian and Brownian relaxation: a review
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paper_title: Induction of apoptotic cell DNA fragmentation in human cells after treatment with hyperthermia.

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The biological significance of apoptosis is becoming increasingly clear. Its relevance in tumor response to treatment as well as recent evidence for its important function as a regulating mechanism in tumorigenesis has also been demonstrated. One of the most prominent biological features of apoptosis is nucleosomal DNA fragmentation. In this communication, we present a study of DNA fragmentation in Raji cells which have been subjected to hyperthermia treatment to induce apoptosis. We found that the induction and onset of fragmentation is swift, and consistent with previous reports that fragmentation must be a rapid event.
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paper_title: The effects of 41°C hyperthermia on the DNA repair protein, MRE11, correlate with radiosensitization in four human tumor cell lines

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Purpose: The goal of this study was to determine if reduced availability of the DNA repair protein, MRE11, for the repair of damaged DNA is a basis for thermal radiosensitization induced by moderate hyperthermia. To test this hypothesis, we measured the total amount of MRE11 DNA repair protein and its heat-induced alterations in four human tumor cell lines requiring different heating times at 41°C to induce measurable radiosensitization.Materials and methods: Human colon adenocarcinoma cell lines (NSY42129, HT29 and HCT15) and HeLa cells were used as the test system. Cells were irradiated immediately after completion of hyperthermia. MRE11 levels in whole cell extract, nuclear extract and cytoplasmic extracts were measured by Western blotting. The nuclear and cytoplasmic extracts were separated by TX100 solubility. The subcellular localization of MRE11 was determined by immunofluorescence staining.Results: The results show that for the human tumor cell lines studied, the larger the endogenous amount of MR...
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paper_title: Thermal Therapy, Part III: Ablation Techniques

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Ablative treatments are gaining increasing attention as an alternative to standard surgical therapies, especially for patients with contraindication or those who refuse open surgery. Thermal ablation is used in clinical applications mainly for treating heart arrhythmias, benign prostate hyperplasia, and nonoperable liver tumors; there is also increasing application to other organ sites, including the kidney, lung, and brain. Potential benefi ts of thermal ablation include reduced morbidity and mortality in comparison with standard surgical resection and the ability to treat nonsurgical patients. The purpose of this review is to outline and discuss the engineering principles and biological responses by which thermal ablation techniques can provide elevation of temperature in organs within the human body. Because of the individual problems associated with each type of treatment, a wide range of ablation techniques have evolved including cryoablation as well as ultrasound, radiofrequency (RF), microwave, and laser ablation. Aspects of each ablation technique, including mechanisms of action, equipment required, selection of eligible patients, treatment techniques, and patient outcomes are presented, along with a discussion of limitations of the techniques and future research directions.
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paper_title: Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer

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AbstractPurpose: We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer.Methods: Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160 ± 5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 °C for 20 min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among ...
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paper_title: Microcalorimetric study of the metabolism of U-937 cells undergoing apoptosis induced by the combined treatment of hyperthermia and chemotherapy

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Hyperthermia is a useful adjunct in cancer therapy, as it can increase the effectiveness and decrease the toxicity of currently available cancer treatments such as chemotherapy and radiation. In this study we determined the power-time curves of U-937 cell line treated by the combination of hyperthermia and Carmofur by using an LKB 2277 Bioactivity Monitor. The maximal thermal power and the heat production were used to evaluate the antitumor effect. Our results show that the combined treatment of hyperthermia and Carmofur had a synergistic antitumor effect, which is consistent with the apoptosis ratio obtained by TUNEL assay. The results also indicate that the metabolic activity of apoptotic cells is lower than that of normal cells. Thus microcalorimetry is a powerful tool in fields of hyperthermia.
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paper_title: Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme

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Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan–Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6–16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma.
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paper_title: Magnetic properties and antitumor effect of nanocomplexes of iron oxide and doxorubicin

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Abstract We present a technology and magneto-mechanical milling chamber for the magneto-mechano-chemical synthesis (MMCS) of magneto-sensitive complex nanoparticles (MNC) comprising nanoparticles Fe 3 O 4 and anticancer drug doxorubicin (DOXO). Magnetic properties of MNC were studied with vibrating magnetometer and electron paramagnetic resonance. Under the influence of mechano-chemical and MMCS, the complex show a hysteresis curve, which is typical for soft ferromagnetic materials. We also demonstrate that Lewis lung carcinoma had a hysteresis loop typical for a weak soft ferromagnet in contrast to surrounding tissues, which were diamagnetic. Combined action of constant magnetic field and radio frequency moderate inductive hyperthermia (RFH) below 40°C and MNC was found to induce greater antitumor and antimetastatic effects as compared to conventional DOXO. Radiospectroscopy shows minimal activity of FeS-protein electron transport chain of mitochondria, and an increase in the content of non-heme iron complexes with nitric oxide in the tumor tissues under the influence of RFH and MNC. From the Clinical Editor This study reports on the top-down synthesis of magneto-sensitive complex nanoparticles comprised of Fe 3 O 4 nanoparticles and doxorubicin. Authors also found that Lewis lung carcinoma had a hysteresis loop typical for a weak soft ferromagnet in contrast to surrounding tissues, which were diamagnetic. Combined action of constant magnetic field and radio frequency induced moderate hyperthermia induced both antitumor and antimetastatic effects greater than conventional DOX alone.
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paper_title: Potential for therapy of drugs and hyperthermia.

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The interaction of hyperthermia (41--45 degrees C) and chemotherapeutic agents frequently results in increased cytotoxicity over that predicted for an additive effect, although to date only a very limited number of drugs have been examined for such a possible interaction. At 42 degrees C, the upper limit of temperature useful for whole-body hyperthermia, the most promising agents of those examined to date appear to be the nitrosoureas and cis-platinum. Insufficient data exist for cyclophosphamide, whose long plasma half-life makes it an attractive candidate. Localized heating seems optimum at higher temperatures (43--45 degrees C). At these temperatures, not only those drugs effective at 42 degrees C but particularly bleomycin and possibly amphotericin B become candidates. No data exist in the literature on possible "thermic sensitizers," i.e., drugs which are noncytotoxic at 37 degrees C but which become effective at elevated temperatures. Two special cases are Adriamycin and actinomycin D. These drugs may be contraindicated for clinical use, since not only synergism but also protection by hyperthermia have been demonstrated, depending upon the time-sequence relationships of the heat and drug treatments.
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paper_title: Arrhenius analysis of heat survival curves from normal and thermotolerant CHO cells.

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The temperature compatible with biphasic hyperthermia-survival curves in Chinese hamster ovary cells was increased from 42.5 to 44°C by acute heat conditioning (10 min, 45°C). An Arrhenius analysis...
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paper_title: Circulatory responses of malignant tumors during hyperthermia

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Abstract The use of hyperthermia (elevation of regional body temperature to 41.5°–45°) as an adjuvant to clinical radiation therapy is becoming accepted in clinical practice at this time. It is, therefore, imperative to define the physiological responses of tumors to this modality. In this article, the effect of hyperthermia on the physiological responses of human and murine tumors are evaluated employing pH, oxygen, and flow ultramicroelectrodes. It is determined that hyperthermia causes a rise in tissue oxygen tension ( T p O 2 ) and blood flow at temperatures up to 41°, with a decrease at higher temperatures. Tumor tissue pH is low (6.8) and decreases during hyperthermia by as much as one unit of pH. The evidence linking these observations and the importance of blood flow modifications are discussed.
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paper_title: Interaction of Heat and Drugs In Vitro and In Vivo

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The intention of this chapter is to review existing experimental data on combinations of cytotoxic drugs and hyperthermia. The focus will be on those drugs which are the most likely candidates for potentiation by hyperthermia, and attention will be drawn to findings which may form a basis for the design of clinical studies.
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paper_title: Hyperthermia Induces Apoptosis in Thymocytes

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Mild hyperthermia (43{degree}C for 1 h) induces extensive double-stranded DNA fragmentation and, at a later time, cell death in murine thymocytes. The cleavage of DNA into oligonucleosome-sized fragments resembles that observed in examples of apoptosis including radiation-induced death of thymocytes. Following hyperthermia, incubation at 37{degree}C is necessary to detect DNA fragmentation, although protein and RNA synthesis do not seem to be required. Two protein synthesis inhibitors, cycloheximide and emetine, and two RNA synthesis inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, do not inhibit DNA fragmentation or cell death in heated thymocytes at concentrations which significantly block these effects in irradiated thymocytes. We have used this difference in sensitivity to show that the DNA fragmentation induced in thymocytes which are irradiated and then heated seems to be caused only by the heating and not by the irradiation.
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paper_title: The cellular and molecular basis of hyperthermia

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Abstract In oncology, the term ‘hyperthermia’ refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40–43 °C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.
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paper_title: Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas.

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The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.
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paper_title: The relationship between heating time and temperature: its relevance to clinical hyperthermia.

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It is well known that for a given level of damage to either cells in vitro or tissues in situ the relationship between temperature and time of application undergoes a transition in the range 42-43 degrees C and that above this temperature a change of 1 degree C is equivalent to a change in heating time by a factor of two. The present study has concentrated on establishing the relationship between time and temperature over a wide range. The investigation is in two parts, i.e. a review of the literature and an experimental study in which the endpoint used was necrosis in the tail of the baby rat. The aim is to provide information which might help solve a major clinical problem, namely the lack of a satisfactory means of relating treatments given with different temperatures for different lengths of time. The difficulty arises because there is no satisfactory definition of heat dose, in this context. The results confirm the relationship given above for temperatures above the transition. However, below the transition a change of 1 degree C is equivalent to a change in heating time by a factor of six. It is suggested that these relationships provide a means of monitoring a treatment in which the temperature does not remain constant and may vary within a heated volume. The method may also be used to compare treatments from different centres. An indication of the considerable uncertainties of the procedure is given.(ABSTRACT TRUNCATED AT 250 WORDS)
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paper_title: Cellular responses to hyperthermia (40–46°C): Cell killing and molecular events

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The goal of this review is to provide a brief introduction to the effects of hyperthermia on cellular structures and physiology. The review focuses on the effects of hyperthermia thought to contribute to the enhancement of cancer therapy namely the mechanisms of cell killing and the sensitization of cells to ionizing radiation or chemotherapeutic agents. Specifically the review addresses four topics: hyperthermia induced cell killing, mathematical models of cell killing, mechanisms of thermal effects in the hyperthermia temperature range and effects on proteins that contribute to resistance to other stresses, i.e., DNA damage. Hyperthermia has significant effects on proteins including unfolding, exposing hydrophobic groups, and aggregation with proteins not directly altered by hyperthermia. Protein aggregation has effects throughout the cell but has a significant impact within the nucleus. Changes in the associations of nuclear proteins particularly those involved in DNA replication cause the stalling of ...
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paper_title: Hyperthermia adds to chemotherapy.

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The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy. Preclinical research reveals that for heat killing and synergistic effects the thermal dose is most critical. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. The induction of genetically defined stress responses can deliver danger signals to activate the host's immune system. The positive results of randomised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer. Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity. In specific clinical settings regional hyperthermia (RHT) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies. In Europe, more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology.
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paper_title: Thermal Therapy, Part 2: Hyperthermia Techniques

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Hyperthermia, the procedure of raising the temperature of a part of or the whole body above normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. Clinical hyperthermia falls into three broad categories, namely, (1) localized hyperthermia, (2) regional hyperthermia, and (3) whole-body hyperthermia (WBH). Because of the various problems associated with each type of treatment, different heating techniques have evolved. In this article, background information on the biological rationale and current status of technologies concerning heating equipment for the application of hyperthermia to human cancer treatment are provided. The results of combinations of other modalities such as radiotherapy or chemotherapy with hyperthermia as a new treatment strategy are summarized. The article concludes with a discussion of challenges and opportunities for the future.
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paper_title: Intracranial Thermotherapy using Magnetic Nanoparticles Combined with External Beam Radiotherapy: Results of a Feasibility Study on Patients with Glioblastoma Multiforme

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We aimed to evaluate the feasibility and tolerability of the newly developed thermotherapy using magnetic nanoparticles on recurrent glioblastoma multiforme. Fourteen patients received 3-dimensional image guided intratumoral injection of aminosilane coated iron oxide nanoparticles. The patients were then exposed to an alternating magnetic field to induce particle heating. The amount of fluid and the spatial distribution of the depots were planned in advance by means of a specially developed treatment planning software following magnetic resonance imaging (MRI). The actually achieved magnetic fluid distribution was measured by computed tomography (CT), which after matching to pre-operative MRI data enables the calculation of the expected heat distribution within the tumor in dependence of the magnetic field strength. Patients received 4–10 (median: 6) thermotherapy treatments following instillation of 0.1–0.7 ml (median: 0.2) of magnetic fluid per ml tumor volume and single fractions (2 Gy) of a radiotherapy series of 16–70 Gy (median: 30). Thermotherapy using magnetic nanoparticles was tolerated well by all patients with minor or no side effects. Median maximum intratumoral temperatures of 44.6°C (42.4–49.5°C) were measured and signs of local tumor control were observed. In conclusion, deep cranial thermotherapy using magnetic nanoparticles can be safely applied on glioblastoma multiforme patients.
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paper_title: Synergistic cell-killing effect of a combination of hyperthermia and heavy ion beam irradiation: in expectation of a breakthrough in the treatment of refractory cancers (review).

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We studied the sensitivity against heavy ion beam and hyperthermia on radioresistant procaryote, Deinococcus radiodurans, for the purpose of cancer therapy. First, we examined the decrease of the survival rate and molecular weight of DNA purified from this cell by acid heat treatment. These decreases were recognized by heating at 55 degrees C below pH 5.0. Then, we assumed that the decrease in survival of D. radiodurans in vivo and damage to its DNA in vitro by acid heating were due to the release of purine rings from the phosphodiester backbone of DNA molecules, i.e., depurination. Second, we investigated the relation between LET (linear energy transfer) and RBE (relative biological effectiveness) on D. radiodurans dry and wet cells using AVF cyclotron at the TIARA facility of JAERI-Takasaki, Japan. These cells were irradiated with carbon (12C5+) ion beam at LET of about 100 keV/microm, neon (20Ne8+) ion beam at LET of about 300 keV/microm and oxygen (16O6+) ion beam at LET of about 400 keV/microm. The peak in the figure of the relation between LET and RBE value was found to increase according to the increase of LET value from 100 keV/microm. Third, we conducted combination treatment with 4.8 kGy of alpha-particles, i.e., boron 10 neutron captured beam induced by Kyoto University Research Nuclear Reactor operated at 5 MW, and hyperthermia at 52 degrees C, which caused the synergistic killing effect on D. radiodurans wet cells. However, being dissimilar to the case of gamma-irradiation, the interval incubation at 30 degrees C in the medium between both treatments could inhibit the recovery of survival.
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paper_title: Thermal Therapy, Part 1: An Introduction to Thermal Therapy

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Thermal therapy is widely known and electromagnetic (EM) energy, ultrasonic waves, and other thermal-conduction-based devices have been used as heating sources. In particular, advances in EM technology have paved the way for promising trends in thermotherapeutical applications such as oncology, physiotherapy, urology, cardiology, ophthalmology, and in other areas of medicine as well. This series of articles is generally written for oncologists, cancer researchers, medical students, biomedical researchers, clinicians, and others who have an interest in this topic. This article reviews key processes and developments in thermal therapy with emphasis on two techniques, namely, hyperthermia [including long-term low-temperature hyperthermia (40-41 degrees C for 6-72 hr), moderate-temperature hyperthermia (42-45 degrees C for 15-60 min), and thermal ablation, or high-temperature hyperthermia (> 50 degrees C for > 4-6 min)]. The article will also provide an overview of a wide range of possible mechanisms and biological effects of heat. This information will be discussed in light of what is known about the degree of temperature rise that is expected from various sources of energy. The review concludes with an evaluation of human exposure risk to EM energy or the corresponding heat, trends in equipment development, and future research directions.
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paper_title: In Vitro Thermochemotherapy of Human Colon Cancer Cells with cis-Dichlorodiammineplatinum(II) and Mitomycin C

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The thermosensitivity of human colon adenocarcinoma (LoVo) cells was investigated as a function of temperature and duration of heating in exponentially growing cultures. At 39-43°, time-dependent survival followed a simple exponential function. D o values decreased progressively with a rise in temperature, from D o at 40° = 38 hr to D o at 42° = 17 hr to D o at 43° = 1.5 hr, thus indicating relative thermoresistance of LoVo cells compared to Chinese hamster ovary cells. Dose-dependent 1-hr survival of LoVo cells treated with cis -dichlorodiammineplatinum(II) and mitomycin C was effectively modified when treatment was conducted under hyperthermic conditions. For both agents and cultures in exponential and stationary growth phases, hyperthermia abolished the initial shoulder portion and steepened the subsequent exponential part of the survival curves for dose-modifying factors at the 10% survival level of 1.5 to 2.0 at 41° and 2.6 to 2.8 at 42°. This significant enhancement of drug-induced cell kill by moderate hyperthermia suggests that thermochemotherapy with mitomycin C and cis -dichlorodiammineplatinum(II) should be tested clinically with both regional and total-body hyperthermia.
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paper_title: Inhibition of repair of radiation-induced damage by mild temperature hyperthermia, referring to the effect on quiescent cell populations

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PurposeWe evaluated the usefulness of mild temperature hyperthermia (MTH) as an inhibitor of the repair of radiation-induced damage in terms of the responses of the total [= proliferating (P) + quiescent (Q)] and Q cell populations in solid tumors in vivo.Materials and methodsSCC VII tumor-bearing mice received a continuous administration of 5-bromo-2′-deoxyuridine (BrdU) to label all P cells. They then underwent high-dose-rate (HDR) γ-ray irradiation immediately followed by MTH or administration of caffeine or wortmannin; alternatively, they underwent reduced-dose rate γ-ray irradiation simultaneously with MTH or administration of caffeine or wortmannin. Nine hours after the start of irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total tumor cell population was determined using tumors that were not pretreated with BrdU.ResultsIn both the total and Q-cell populations, especially the latter, MTH efficiently suppressed the reduction in sensitivity caused by leaving an interval between HDR irradiation and the assay and decreasing the irradiation dose rate, as well as the combination with wortmannin administration.ConclusionFrom the viewpoint of solid tumor control as a whole, including intratumor Q-cell control, MTH is useful for suppressing the repair of both potentially lethal and sublethal damage.
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paper_title: Effect of hyperthermia on malignant cellsin vivo: A review and a hypothesis

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The relevant literature is reviewed in an attempt to clarify the mechanism of heat-dependent tumor cell destruction in vivo. Malignant cells in vivo appear to be selectively destroyed by hyperthermia in the range of 41-43 degrees C. Heat evidently affects nuclear function, expressed by an inhibited RNA, DNA and protein synthesis and characteristic arrest or delay of cells in certain locations of the cell cycle. However, as these effects appear to be reversible and are observed in normal cells as well as malignant cells, they probably do not explain the hyperthermic induced selective in vivo destruction of malignant cells. Heat-induced cytoplasmic damage appears to be of more importance. Increased lysosomal activation is observed, and is further intensified by a relatively increased anaerobic glycolysis which develops selectively in tumor cells. A hypothesis is proposed and discussed which explains the marked and selective in vivo tumor cell destruction as a consequence of the enhancing effect on the cytoplasmic damage of certain environmental factors (e.g. increased acidity, hypoxia and insufficient nutrition.
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paper_title: Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermia and/or nicotinamide: reference to effect on quiescent tumour cells.

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C3H/He and Balb/c mice bearing SCC VII or EMT6/KU tumours received continuous administration of 5-bromo-2'-deoxyuridine (BrdU) for 5 days to label all proliferating (P) cells. The tumours were locally heated at 40 degrees C for 60 min and/or the tumour-bearing mice received intraperitoneal injection of nicotinamide, and then tirapazamine (TPZ) was injected intraperitoneally. Sixty minutes after TPZ injection, the tumours were excised, minced and trypsinized. The tumour cell suspensions were incubated with cytochalasin-B (a cytokinesis-blocker), and the micronucleus (MN) frequency in cells without BrdU labelling (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumour cells was determined from the tumours that were not pretreated with BrdU. The cytotoxicity of TPZ was evaluated in terms of the frequency of induced micronuclei in binuclear tumour cells (= MN frequency). In both tumour systems, the MN frequencies of Q cells were greater than those of total tumour cell populations. Mild heat treatment elevated the MN frequency in total and Q cells in both tumour systems, but the effect was more marked in Q cells. In total cells, mild heat treatment increased the MN frequency in EMT6/KU tumour cells more markedly than in SCC VII tumour cells. In contrast, in both tumour systems, nicotinamide decreased the MN frequency in both cell populations, with a greater influence on the total cells. The combination of TPZ and mild heat treatment may be useful for sensitizing tumour cells in vivo, including Q cells.
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paper_title: Cell death induced in a murine mastocytoma by 42-47 degrees C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load.

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The pathogenesis of heat-induced cell death is controversial. Categorizing the death occurring after various heat loads as either apoptosis or necrosis might help to elucidate this problem, since it has been shown that these two processes differ in their mode of initiation as well as in their morphological and biochemical features. Log-phase cultures of mastocytoma P-815 x 2.1 were heated at temperatures ranging from 42 to 47 degrees C for 30 min. After 42 degrees C heating a slight increase in apoptosis was observed morphologically. However, after heating at 43, 43.5 and 44 degrees C, there was marked enhancement of apoptosis, and electrophoresis of DNA showed characteristic internucleosomal cleavage. With heating at 45 degrees C both apoptosis and necrosis were enhanced, whereas at 46 and 47 degrees C only necrosis was produced. DNA extracted from the 46 and 47 degrees C cultures showed virtually no degradation, which contrasts with the random DNA breakdown observed in necrosis produced by other types of injury; lysosomal enzymes released during heat-induced necrosis may be inactivated at the higher temperatures. It is suggested that apoptosis following heating may be triggered either by a limited increase in cytosolic calcium levels resulting from mild membrane changes or by DNA damage. Necrosis, on the other hand, is likely to be a consequence of severe membrane disruption.
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paper_title: Implication of Blood Flow in Hyperthermic Treatment of Tumors

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Tumor blood flow varies significantly depending on the type, age, and size of tumors. Furthermore, the distribution of blood perfusion in tumors is quite heterogeneous. Blood flow in tumors may or may not be greater than that in the surrounding normal tissues at normothermic conditions. When heated at 41-430C, tumor blood flow either remains unchanged or increases slightly, usually by a factor of less than 2. The newly formed tumor vessels appear to be so vulnerable to heat that the blood flow decreases at 42-43' C in most of the animal tumors studied so far. By contrast, the blood flow in normal tissues, e. g., skin and muscle, increases by a factor of 3-20 upon heating at 42-450C. Consequently, the heat dissipation by blood flow becomes greater in normal tissues than in tumors during heating, and thereby a greater temperature rise in tumors may occur, resulting in greater damage in tumor relative to normal tissues. The intrinsically acidic intratumor environment becomes further acidic upon heating and accentuates the thermal damage on the tumor cells. Blood perfusion appears to be implicated in such a heat-induced increase in the intratumor acidity.
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paper_title: Thermotherapy using magnetic nanoparticles combined with external radiation in an orthotopic rat model of prostate cancer

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BACKGROUND ::: We evaluated the effects of thermotherapy using magnetic nanoparticles, also referred to as magnetic fluid hyperthermia (MFH), combined with external radiation, in the Dunning model of prostate cancer. ::: ::: ::: METHODS ::: Orthotopic tumors were induced in 96 male Copenhagen rats. Animals were randomly allocated to eight groups, including controls and groups for dose-finding studies of external radiation. Treatment groups received two serial thermotherapy treatments following a single intratumoral injection of magnetic fluid or thermotherapy followed by external radiation (10 Gy). On day 20, after tumor induction, tumor weights in the treatment and control groups were compared and iron measurements in selected organs were carried out. ::: ::: ::: RESULTS ::: Mean maximal and minimal intratumoral temperatures obtained were 58.7 degrees C (centrally) and 42.7 degrees C (peripherally) during the first thermotherapy and 55.4 degrees C and 42.3 degrees C, respectively, during the second of two treatment sessions. Combined thermotherapy and radiation with 20 Gy was significantly more effective than radiation with 20 Gy alone and reduced tumor growth by 87.5-89.2% versus controls. Mean iron content in the prostates on day 20 was 87.5% of the injected dose of ferrites, whereas only 2.5% was found in the liver. ::: ::: ::: CONCLUSIONS ::: An additive effect was demonstrated for the combined treatment at a radiation dose of 20 Gy, which was equally effective in inhibiting tumor growth as radiation alone with 60 Gy. Serial heat treatments were possible without repeated injection of magnetic fluid. The optimal treatment schedules of this combination regarding temperatures, radiation dose, and fractionation need to be defined in further experimental studies.
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paper_title: Cellular effects of hyperthermia: relevance to the minimum dose for thermal damage.

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The specific mechanism of cell killing by hyperthermia is unknown, but the high activation energy of cell killing and other responses to hyperthermia suggest that protein denaturation is the rate-limiting step. Protein denaturation can be directly monitored by differential scanning calorimetry and in general there is a good correlation between protein denaturation and cellular response. Approximately 5% denaturation is necessary for detectable killing. Protein denaturation leads to the aggregation of both denatured and native protein with multiple effects on cellular function.
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paper_title: Differential response of normal and tumor microcirculation to hyperthermia.

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RBC velocity and vessel lumen diameter were measured in individual microvessels in normal (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in a transparent rabbit ear chamber. Blood flow rates were determined before, during, and after local hyperthermia treatments at 40-52 degrees for 1 hr. Blood flow in normal tissue increased dramatically with temperature, but stasis occurred at higher temperatures and/or longer durations of heating. In tumors, blood flow rate did not increase as much, and stasis occurred at lower levels of hyperthermia. Both the magnitude and the time of maximum flow appeared to be bimodal functions of temperature. That is, both of these parameters increased with temperature up to a certain critical temperature, and then decreased at higher temperatures. This critical temperature was approximately 45.7 degrees in normal tissue and 43.0 degrees in tumors. Normal tissue required temperatures greater than 47 degrees to bring about vascular stasis in less than 1 hr, while stasis occurred in tumors in the same time frame at temperatures greater than 41 degrees. Normal tissue could increase its maximum flow capacity up to 6 times its preheating value, while neoplastic tissue could only double its maximum flow capacity. This differential flow response in individual microvessels was used to develop a theoretical framework relating various mechanisms of blood flow modifications due to hyperthermia.
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paper_title: Arrhenius relationships from the molecule and cell to the clinic.

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There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffefct induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43-44 degrees C up to about 57 degrees C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1 degrees C. This same time-temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46 degrees C to either 43 or 49 degrees C. For cytotoxic temperatures < 43-44 degrees C, R for mammalian cells and tissues is about 4-6. Many factors change the absolute heat sensitivity of mammalian cells by about 1 degrees C, but these factors have little effect on Rs, although the transition in R at 43-44 degrees C may be eliminated or shifted by about 1 degrees C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1-1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30-60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equiv min at 43 degrees C (EM43). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43 degrees C, viz., CEM43. This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumours indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic.(ABSTRACT TRUNCATED AT 400 WORDS)
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paper_title: Hyperthermic radiosensitization: mode of action and clinical relevance.

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PURPOSE ::: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. ::: ::: ::: SUMMARY ::: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates the cellular action of radiation by interfering with the cells' capability to deal with radiation-induced DNA damage. For ionizing irradiation, heat inhibits the repair of all types of DNA damage. Genetic and biochemical data suggest that the main pathways for DNA double-strand break (DSB) rejoining, non-homologous end-joining and homologous recombination, are not the likely primary targets for heat-induced radiosensitization. Rather, heat is suggested to affect primarily the religation step of base excision repair. Subsequently additional DSB arise during the DNA repair process in irradiated and heated cells and these additional DSB are all repaired with slow kinetics, the repair of which is highly error prone. Both mis- and non-rejoined DSB lead to an elevated number of lethal chromosome aberrations, finally causing additional cell killing. Heat-induced inhibition of DNA repair is considered not to result from altered signalling or enzyme inactivation but rather from alterations in higher-order chromatin structure. Although, the detailed mechanisms are not yet known, a substantial body of indirect and correlative data suggests that heat-induced protein aggregation at the level of attachment of looped DNA to the nuclear matrix impairs the accessibility of the damaged DNA for the repair machinery or impairs the processivity of the repair machinery itself. ::: ::: ::: CONCLUSION ::: Since recent phase III clinical trials have shown significant benefit of adding hyperthermia to radiotherapy regimens for a number of malignancies, it will become more important again to determine the molecular effects underlying this success. Such information could eventually also improve treatment quality in terms of patient selection, improved sequencing of the heat and radiation treatments, the number of heat treatments, and multimodality treatments (i.e. thermochemoradiotherapy).
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paper_title: THERMAL DOSE DETERMINATION IN CANCER THERAPY

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Abstract With the rapid development of clinical hyperthermia for the treatment of cancer either alone or in conjunction with other modalities, a means of measuring a thermal dose in terms which are clinically relevant to the biological effect is needed. A comparison of published data empirically suggests a basic relationship that may be used to calculate a “thermal dose.” From a knowledge of the temperature during treatment as a function of time combined with a mathematical description of the time-temperature relationship, an estimate of the actual treatment calculated as an exposure time at some reference temperature can be determined. This could be of great benefit in providing a real-time accumulated dose during actual patient treatment. For the purpose of this study, a reference temperature of 43°C has been arbitrarily chosen to convert all thermal exposures to “equivalent-minutes” at this temperature. This dose calculation can be compared to an integrated calculation of the “degree-minutes” to determine its prognostic ability. The time-temperature relationship upon which this equivalent dose calculation is based does not predict, nor does it require, that different tissues have the same sensitivity to heat. A computer program written in FORTRAN is included for performing calculations of both equivalent-minutes (t 43 ) and degree-minutes (t dm43 ). Means are provided to alter the reference temperature, the Arrhenius “break” temperature and the time-temperature relationship both above and below the “break” temperature. In addition, the effect of factors such as step-down heating, thermotolerance, and physiological conditions on thermal dose calculations are discussed. The equations and methods described in this report are not intended to represent the only approach for thermal dose estimation; instead, they are intended to provide a simple but effective means for such calculations for clinical use and to stimulate efforts to evaluate data in terms of therapeutically useful thermal units.
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paper_title: Investigations on the possibility of a thermic tumour therapy—I.: Short-wave treatment of a transplanted isologous mouse mammary carcinoma☆☆☆

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The existing literature on studies of the inhibitory effect of moderate heat doses on malignant tumours is briefly reviewed. ::: ::: An experimental technique of heat treatment of mouse tumours in vivo under accurate control of the intratumoural temperature is described. ::: ::: In experiments with an isologous transplantable mouse mammary carcinoma, controlled application of a moderate heat dose led, in many cases, to a permanent cure of the transplanted tumour without causing any damage to the surrounding normal tissue. ::: ::: The necessary heat doses in the temperature range of 41·5 to 43·5°C are worked out revealing a definite relationship between temperature and exposure time. ::: ::: The heat treatment induces distinct histological changes in the tumour cells, whereas it does not cause any damage to the stromal and vascular cells in the tumour, or to the surrounding normal tissue. ::: ::: Immediately after the heat application, definite changes were revealed in the mitochondria and lysosomes of the tumour cells. These changes increased in intensity with the size of the heat dose and become more pronounced within a few hours or days. Within the first few hours, changes in the nuclei of the tumour cells and in chromosomal and nucleolar chromatin developed, with some variation in the individual cells. 24 hr after the application of a curative dose, all tumour cells showed severe injury. After smaller doses the reaction to the heat was less intense, with variations in the individual cells, and several tumour cells did not show any signs of lethal injury. ::: ::: Autolytic disintegration of the heat-damaged tumour cells occurs very rapidly. The connective tissue of the stroma increases markedly in volume, and a scar forms. ::: ::: The histological examination did not reveal all details of the process, but in the light of biochemical observations, it is reasonable to assume that the direct effect of heat is due to an elective activation of the acid hydrolases localized in the lysosomes of the tumour cells.
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paper_title: Re-setting the biologic rationale for thermal therapy

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This review takes a retrospective look at how hyperthermia biology, as defined from studies emerging from the late 1970s and into the 1980s, mis-directed the clinical field of hyperthermia, by placing too much emphasis on the necessity of killing cells with hyperthermia in order to define success. The requirement that cell killing be achieved led to sub-optimal hyperthermia fractionation goals for combinations with radiotherapy, inappropriate sequencing between radiation and hyperthermia and goals for hyperthermia equipment performance that were neither achievable nor necessary. The review then considers the importance of the biologic effects of hyperthermia that occur in the temperature range that lies between that necessary to kill substantial proportions of cells and normothermia (e.g. 39–42°C for 1 h). The effects that occur in this temperature range are compelling including—inhibition of radiation-induced damage repair, changes in perfusion, re-oxygenation, effects on macromolecular and nanoparticle ...
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paper_title: Physiological mechanisms underlying heat-induced radiosensitization

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The objective of this review is to evaluate hyperthermia related changes in tumor physiologic parameters and their relevance for tumor radiosensitization with particular emphases on tumor oxygenation. Elevation of temperature above the physiological level causes changes in blood flow, vascular permeability, metabolism, and tumor oxygenation. These changes in addition to the cellular effects such as direct cytotoxicity, inhibition of potentially lethal damage and sublethal damage repair, have an important influence on the efficacy of radiotherpay. There is now clear evidence that in a variety of rodent and canine, as well as human tumors, the changes in tumor oxygenation status caused by hyperthermia are temperature dependent and this relationship may greatly influence the response of tumors to thermo-radiotherapy. The improvement of tumor oxygenation after mild hyperthermia, which often lasts for as long as 24–48 h after heating, may increase the likelihood of a positive response of tumors to radiation th...
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paper_title: Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future.

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Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.
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paper_title: Thermal dose and time—temperature factors for biological responses to heat shock

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The application of hyperthermia in human cancer therapy, especially by radiotherapists who are accustomed to prescribing ionizing radiation treatments in physical dose units, has stimulated workers in this area to consider the possibility and utility of defining a unit of ‘thermal dose’. Previous thermal dose definitions have, primarily, been based on biological isoeffect response relationships, which attempt to relate exposure times that elicit a given biological response at one temperature to exposure times at another temperature that elicit the same biological response. This ‘equivalent time’ method is shown to have certain limitations. For both 42.4 and 45°C hyperthermia, these relationships accurately describe cell survival responses only when the heating rate is rapid (< 0.5°C min−1 from ambient to hyperthermic temperature). Further, the form of these isoeffect relationships appears to be temperature range and cell/tissue-type dependent, and it is suggested that these relationships be referred to as...
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paper_title: Differential thermal sensitivity of tumour and normal tissue microvascular response during hyperthermia

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The goal of this study was to investigate the heat sensitivity of the microcirculation in normal C3H murine leg muscle and a variety of transplanted tumour lines (KHT, SCC-VII, RIF-1, C3H mouse mammary carcinoma, two human mammary carcinomas MDA-468 and S5). Clearance rate of a radioactive tracer monitored following an intra-tissue injection was used as a measurement of microvascular integrity during heat treatment. Clearance rate in all tumours studied was significantly lower after 1 h of heating at 44°C than the initial pretreatment clearance rate. Response of normal muscle differed from that of tumours in that the clearance rate after 1 h of heating at 44°C was similar to the initial clearance rate. Vasculature in the KHT fibrosarcoma was more sensitive to heat treatment than that in other tumours. In response to a heat treatment at 43, 44, 45, and 46°C the same level of microvascular damage occurred in half the time in KHT fibrosarcoma than in normal muscle. Furthermore, vascular damage in both muscle...
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paper_title: Modification of Cell Lethality at Elevated Temperatures The pH Effect

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The lethal response of Chinese hamster ovary cells to hyperthermia was determined at selected extracellular pH. Decreasing pH from 7.6 to 6.7 increased the lethal response of cells over the temperature range of 41 to 44°C. Cell viability was not effected over this pH range at 37°C. The pH sensitizing affect was most prominent at temperatures which were marginally lethal at normal pH (7.4). Four hours of exposure to 42°C decreased survival to 10% at pH 7.4 and 0.01% at pH 6.7. Enhanced cell killing was observed when the cells were exposed to reduced pH and elevated temperatures simultaneously. Prolonging the time of pH exposure before and after hyperthermia did not influence survival. High-density culturing increased the sensitivity of cells to hyperthermia. This affect was due to metabolic acidification of the medium and could be reversed by adjusting the pH.
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paper_title: EGFR-targeted magnetic nanoparticle heaters kill cancer cells without a perceptible temperature rise.

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It is currently believed that magnetic nanoparticle heaters (MNHs) can kill cancer cells only when the temperature is raised above 43 °C due to energy dissipation in an alternating magnetic field. On the other hand, simple heat conduction arguments indicate that in small tumors or single cells the relative rates of energy dissipation and heat conduction result in a negligible temperature rise, thus limiting the potential of MNHs in treating small tumors and metastatic cancer. Here we demonstrate that internalized MNHs conjugated to epidermal growth factor (EGF) and which target the epidermal growth factor receptor (EGFR) do result in a significant (up to 99.9%) reduction in cell viability and clonogenic survival in a thermal heat dose dependent manner, without the need for a perceptible temperature rise. The effect appears to be cell type specific and indicates that magnetic nanoparticles in alternating magnetic fields may effectively kill cancer cells under conditions previously considered as not possible.
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paper_title: Thermotherapy of Prostate Cancer Using Magnetic Nanoparticles: Feasibility, Imaging, and Three-Dimensional Temperature Distribution

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Abstract Objectives To investigate the feasibility of thermotherapy using biocompatible superparamagnetic nanoparticles in patients with locally recurrent prostate cancer and to evaluate an imaging-based approach for noninvasive calculations of the three-dimensional temperature distribution. Methods Ten patients with locally recurrent prostate cancer following primary therapy with curative intent were entered into a prospective phase 1 trial. The magnetic fluid was injected transperineally into the prostates according to a preplan. Patients received six thermal therapies of 60-min duration at weekly intervals using an alternating magnetic field applicator. A method of three-dimensional thermal analysis based on computed tomography (CT) of the prostates was developed and correlated with invasive and intraluminal temperature measurements. The sensitivity of nanoparticle detection by means of CT was investigated in phantoms. Results The median detection rate of iron oxide nanoparticles in tissue specimens using CT was 89.5% (range: 70–98%). Maximum temperatures up to 55°C were achieved in the prostates. Median temperatures in 20%, 50%, and 90% of the prostates were 41.1°C (range: 40.0–47.4°C), 40.8°C (range: 39.5–45.4°C), and 40.1°C (range: 38.8–43.4°C), respectively. Median urethral and rectal temperatures were 40.5°C (range: 38.4–43.6°C) and 39.8°C (range: 38.2–43.4°C). The median thermal dose was 7.8 (range: 3.5–136.4) cumulative equivalent minutes at 43°C in 90% of the prostates. Conclusion The heating technique using magnetic nanoparticles was feasible. Hyperthermic to thermoablative temperatures were achieved in the prostates at 25% of the available magnetic field strength, indicating a significant potential for higher temperatures. A noninvasive thermometry method specific for this approach could be developed, which may be used for thermal dosimetry in future studies.
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paper_title: Normal tissue and solid tumor effects of hyperthermia in animal models and clinical trials.

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Localized hyperthermia therapy by high-energy radio-frequency waves was evaluated in malignant and adjacent normal tissue of 30 patients with 10 types of cancer. Hyperthermia was delivered to superficial and deep visceral cancers in awake patients who had refractory disease. Histological and clinical responses were recorded serially. Toxicity tests in dogs, sheep, and pigs showed that progressive necrosis of normal and cancer tissue occurred at temperatures above 45 degrees C (113 degrees F). However, as normal tissues approached this temperature, intrinsic heat dissipation occurred (possibly due to augmented blood flow) so that temperatures below 45 degrees C could be maintained, whereas most solid tumors did not have this adaptive capacity and could be heated to 50 degrees C (122 degrees F) with virtually no injury to normal organs, s.c. tissue, or skin. To date, 69 treatments have been administered to 36 tumors in the 30 patients. Selective heating was observed in both primary and metastatic tumors located in surface tissues and internal organs. Response appeared to be related to tumor size in that differential heating was possible more often in the larger lesions. In tumors successfully heated, moderate to marked necrosis occurred. Radio-frequency hyperthermia appears to be a safe and potentially useful form of therapy for selected cancer patients. While other cancer treatments are more effective for small tumors, hyperthermia may be uniquely beneficial against larger lesions.
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paper_title: Nearly complete regression of tumors via collective behavior of magnetic nanoparticles in hyperthermia

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One potential cancer treatment selectively deposits heat to the tumor through activation of magnetic nanoparticles inside the tumor. This can damage or kill the cancer cells without harming the surrounding healthy tissue. The properties assumed to be most important for this heat generation (saturation magnetization, amplitude and frequency of external magnetic field) originate from theoretical models that assume non-interacting nanoparticles. Although these factors certainly contribute, the fundamental assumption of 'no interaction' is flawed and consequently fails to anticipate their interactions with biological systems and the resulting heat deposition. Experimental evidence demonstrates that for interacting magnetite nanoparticles, determined by their spacing and anisotropy, the resulting collective behavior in the kilohertz frequency regime generates significant heat, leading to nearly complete regression of aggressive mammary tumors in mice.
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paper_title: Medical application of functionalized magnetic nanoparticles.

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Since magnetic particles have unique features, the development of a variety of medical applications has been possible. The most unique feature of magnetic particles is their reaction to a magnetic force, and this feature has been utilized in applications such as drug targeting and bioseparation including cell sorting. Recently, magnetic nanoparticles have attracted attention because of their potential as contrast agents for magnetic resonance imaging (MRI) and heating mediators for cancer therapy (hyperthermia). Magnetite cationic liposomes (MCLs), one of the groups of cationic magnetic particles, can be used as carriers to introduce magnetite nanoparticles into target cells since their positively charged surface interacts with the negatively charged cell surface; furthermore, they find applications to hyperthermic treatments. Magnetite nanoparticles conjugated with antibodies (antibody-conjugated magnetoliposomes, AMLs) are also applied to hyperthermia and have enabled tumor-specific contrast enhancement in MRI via systemic administration. Since magnetic nanoparticles are attracted to a high magnetic flux density, it is possible to manipulate cells labeled with magnetic nanoparticles using magnets; this feature has been applied in tissue engineering. Magnetic force and MCLs were used to construct multilayered cell structures and a heterotypic layered 3D coculture system. Thus, the applications of these functionalized magnetic nanoparticles with their unique features will further improve medical techniques.
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paper_title: Tumor irradiation with intense ultrasound

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Tumors implanted in the hamster flank have been irradiated in vivo with intense focused ultrasound at a spatial peak intensity of 907 W/cm2. A matrix of points was irradiated under c.w. conditions through the central plane of the tumor and perpendicular to the longitudinal axis of the sound field. A center spacing of 4 mm between matrix points and a time-on period of 2.5 sec at each point produced no cures. A spacing distance of 2 mm with 7 sec time-on period at each point increased mean survival time in non-cured animals and produced a cure rate of 29.4%. Combining the second regime of ultrasound treatment with administration of a chemotherapeutic agent (BCNU) 24 hr after irradiation did not increase mean survival time in the non-cured animals compared to the BCNU non-irradiated shams; however, the cure rate increased to 40%. Secondary tumors which were not seen in any ultrasound shams or controls were observed in all other regimes including BCNU non-irradiated shams. The incidence of secondary tumors was inversely related to the cure rate.
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paper_title: Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique.

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The aim of this pilot study was to evaluate whether the technique of magnetic fluid hyperthermia can be used for minimally invasive treatment of prostate cancer. This paper presents the first clinical application of interstitial hyperthermia using magnetic nanoparticles in locally recurrent prostate cancer. Treatment planning was carried out using computerized tomography (CT) of the prostate. Based on the individual anatomy of the prostate and the estimated specific absorption rate (SAR) of magnetic fluids in prostatic tissue, the number and position of magnetic fluid depots required for sufficient heat deposition was calculated while rectum and urethra were spared. Nanoparticle suspensions were injected transperineally into the prostate under transrectal ultrasound and flouroscopy guidance. Treatments were delivered in the first magnetic field applicator for use in humans, using an alternating current magnetic field with a frequency of 100 kHz and variable field strength (0-18 kA m(-1)). Invasive thermometry of the prostate was carried out in the first and last of six weekly hyperthermia sessions of 60 min duration. CT-scans of the prostate were repeated following the first and last hyperthermia treatment to document magnetic nanoparticle distribution and the position of the thermometry probes in the prostate. Nanoparticles were retained in the prostate during the treatment interval of 6 weeks. Using appropriate software (AMIRA), a non-invasive estimation of temperature values in the prostate, based on intra-tumoural distribution of magnetic nanoparticles, can be performed and correlated with invasively measured intra-prostatic temperatures. Using a specially designed cooling device, treatment was well tolerated without anaesthesia. In the first patient treated, maximum and minimum intra-prostatic temperatures measured at a field strength of 4.0-5.0 kA m(-1) were 48.5 degrees C and 40.0 degrees C during the 1st treatment and 42.5 degrees C and 39.4 degrees C during the 6th treatment, respectively. These first clinical experiences prompted us to initiate a phase I study to evaluate feasibility, toxicity and quality of life during hyperthermia using magnetic nanoparticles in patients with biopsy-proven local recurrence of prostate cancer following radiotherapy with curative intent. To the authors' knowledge, this is the first report on clinical application of interstitial hyperthermia using magnetic nanoparticles in the treatment of human cancer.
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paper_title: Progress in applications of magnetic nanoparticles in biomedicine

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A progress report is presented on a selection of scientific, technological and commercial advances in the biomedical applications of magnetic nanoparticles since 2003. Particular attention is paid to (i) magnetic actuation for in vitro non-viral transfection and tissue engineering and in vivo drug delivery and gene therapy, (ii) recent clinical results for magnetic hyperthermia treatments of brain and prostate cancer via direct injection, and continuing efforts to develop new agents suitable for targeted hyperthermia following intravenous injection and (iii) developments in medical sensing technologies involving a new generation of magnetic resonance imaging contrast agents, and the invention of magnetic particle imaging as a new modality. Ongoing prospects are also discussed.
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paper_title: High intensity focused ultrasound for the treatment of rat tumours

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Discrete implanted liver tumours in the rat have been exposed to arrays of 1.7 MHz ultrasound lesions. Focal peak intensities in the range 1.4-3.5 kWcm-2 were used for an exposure time of 10 s. It has been demonstrated that where the whole tumour volume was exposed to the focused ultrasound beam, no evidence of tumour growth could be detected histologically. Where the ultrasonic lesion array was not contiguous, regrowth occurred. Preliminary histological studies confirmed this finding.
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paper_title: Magnetic nanoparticle design for medical diagnosis and therapy

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Magnetic nanoparticles have attracted attention because of their current and potential usefulness as contrast agents for magnetic resonance imaging (MRI) or colloidal mediators for cancer magnetic hyperthermia. This review examines these in vivo applications through an understanding of the involved problems and the current and future possibilities for resolving them. A special emphasis is made on magnetic nanoparticle requirements from a physical viewpoint (e.g. relaxivity for MRI and specific absorption rate for hyperthermia), the factors affecting their biodistribution (e.g. size, surface hydrophobic/hydrophilic balance, etc.) and the solutions envisaged for enhancing their half-life in the blood compartment and targeting tumour cells.
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paper_title: Magnetic fluid hyperthermia (MFH)reduces prostate cancer growth in the orthotopic Dunning R3327 rat model

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BACKGROUND ::: ::: Magnetic fluid hyperthermia (MFH) is a new technique for interstitial hyperthermia or thermoablation based on AC magnetic field-induced excitation of biocompatible superparamagnetic nanoparticles. Preliminary studies in the Dunning tumor model of prostate cancer have demonstrated the feasibility of MFH in vivo. To confirm these results and evaluate the potential of MFH as a minimally invasive treatment of prostate cancer we carried out a systematic analysis of the effects of MFH in the orthotopic Dunning R3327 tumor model of the rat. ::: ::: ::: ::: METHODS ::: ::: Orthotopic tumors were induced by implantation of MatLyLu-cells into the prostates of 48 male Copenhagen rats. Animals were randomly allocated to 4 groups of 12 rats each, including controls. Treatment animals received two MFH treatments following a single intratumoral injection of a magnetic fluid. Treatments were carried out on days 10 and 12 after tumor induction using an AC magnetic field applicator system operating at a frequency of 100 kHz and a variable field strength (0–18 kA/m). On day 20, animals were sacrificed and tumor weights in the treatment and control groups were compared. In addition, tumor growth curves were generated and histological examinations and iron measurements in selected organs were carried out. ::: ::: ::: ::: RESULTS ::: ::: Maximum intratumoral temperatures of over 70°C could be obtained with MFH at an AC magnetic field strength of 18 kA/m. At a constant field strength of 12.6 kA/m, mean maximal and minimal intratumoral temperatures recorded were 54.8°C (centrally) and 41.2°C (peripherally). MFH led to an inhibition of tumor growth of 44%–51% over controls. Mean iron content in the prostates of treated and untreated (injection of magnetic fluids but no AC magnetic field exposure) animals was 82.5%, whereas only 5.3% of the injected dose was found in the liver, 1.0% in the lung, and 0.5% in the spleen. ::: ::: ::: ::: CONCLUSIONS ::: ::: MFH led to a significant growth inhibition in this orthotopic model of the aggressive MatLyLu tumor variant. Intratumoral deposition of magnetic fluids was found to be stable, allowing for serial MFH treatments without repeated injection. The optimal treatment schedules and temperatures for MFH need to be defined in further studies. © 2005 Wiley-Liss, Inc.
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paper_title: Magnetic fluid hyperthermia inhibits the growth of breast carcinoma and downregulates vascular endothelial growth factor expression

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The application of magnetic fluid hyperthermia (MFH) with nanoparticles has been shown to inhibit tumor growth in several animal models. However, the feasibility of using MFH in vivo to treat breast cancer is uncertain, and the mechanism is unclear. In the present study, it was observed that the intratumoral administration of MFH induced hyperthermia significantly in rats with Walker-265 breast carcinomas. The hyperthermia treatment with magnetic nanoparticles inhibited tumor growth in vivo and promoted the survival of the tumor-bearing rats. Furthermore, it was found that MFH treatment downregulated the protein expression of vascular endothelial growth factor (VEGF) in the tumor tissue, as observed by immunohistochemistry. MFH treatment also decreased the gene expression of VEGF and its receptors, VEGF receptor 1 and 2, and inhibited angiogenesis in the tumor tissues. Taken together, these results indicate that the application of MFH with nanoparticles is feasible for the treatment of breast carcinoma. The MFH-induced downregulation of angiogenesis may also contribute to the induction of an anti-tumor effect.
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paper_title: Status of hyperthermia in the treatment of advanced liver cancer.

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The vast majority of patients with malignant liver tumors have inoperable disease. These patients must rely on chemotherapy, radiotherapy, and various locoregional treatments. Although these treatments have demonstrated encouraging response rates, symptom palliation and occasional down staging of tumors, their impact on survival is minor. As a result there has been renewed interest in hyperthermia as a treatment option. This study reviews the current modalities of hyperthermia in terms of clinical results, side effects, limitations, and therapeutic standing.
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paper_title: Theoretical predictions for spatially-focused heating of magnetic nanoparticles guided by magnetic particle imaging field gradients

paper_content:

Magnetic nanoparticles in alternating magnetic fields (AMFs) transfer some of the field's energy to their surroundings in the form of heat, a property that has attracted significant attention for use in cancer treatment through hyperthermia and in developing magnetic drug carriers that can be actuated to release their cargo externally using magnetic fields. To date, most work in this field has focused on the use of AMFs that actuate heat release by nanoparticles over large regions, without the ability to select specific nanoparticle-loaded regions for heating while leaving other nanoparticle-loaded regions unaffected. In parallel, magnetic particle imaging (MPI) has emerged as a promising approach to image the distribution of magnetic nanoparticle tracers in vivo, with sub-millimeter spatial resolution. The underlying principle in MPI is the application of a selection magnetic field gradient, which defines a small region of low bias field, superimposed with an AMF (of lower frequency and amplitude than those normally used to actuate heating by the nanoparticles) to obtain a signal which is proportional to the concentration of particles in the region of low bias field. Here we extend previous models for estimating the energy dissipation rates of magnetic nanoparticles in uniform AMFs to provide theoretical predictions of how the selection magnetic field gradient used in MPI can be used to selectively actuate heating by magnetic nanoparticles in the low bias field region of the selection magnetic field gradient. Theoretical predictions are given for the spatial decay in energy dissipation rate under magnetic field gradients representative of those that can be achieved with current MPI technology. These results underscore the potential of combining MPI and higher amplitude/frequency actuation AMFs to achieve selective magnetic fluid hyperthermia (MFH) guided by MPI.
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paper_title: Selective inductive heating of lymph nodes.

paper_content:

Selective Inductive Heating of Lymph Nodes R. GILCHRIST;RICHARD MEDAL;WILLIAM SHOREY;RUSSELL HANSELMAN;JOHN PARROTT;C. TAYLOR; Annals of Surgery
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paper_title: Use of magnetic nanoparticle heating in the treatment of breast cancer.

paper_content:

Magnetic nanoparticles are promising tools for the minimal invasive elimination of small tumours in the breast using magnetically-induced heating. The approach complies with the increasing demand for breast conserving therapies and has the advantage of offering a selective and refined tuning of the degree of energy deposition allowing an adequate temperature control at the target. The biophysical basis of the approach, the magnetic and structural properties of magnetic nanoparticles are reviewed. Results with model targets and in vivo experiments in laboratory animals are reported.
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paper_title: High Therapeutic Efficiency of Magnetic Hyperthermia in Xenograft Models Achieved with Moderate Temperature Dosages in the Tumor Area

paper_content:

Purpose ::: Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.
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paper_title: Radiofrequency Ablation of Malignant Liver Tumors

paper_content:

Background: Radiofrequency ablation (RFA) is being used to treat primary and metastatic liver tumors. The indications, treatment planning, and limitations of hepatic RFA must be defined and refined by surgeons treating hepatic malignancies. Methods: A review of the experience using RFA to treat unresectable primary and secondary hepatic malignancies at the University of Texas M. D. Anderson Cancer Center in Houston, Texas, and the G. Pascale National Cancer Institute in Naples, Italy, is provided. Patient selection, treatment approach, local recurrence rates, and overall cancer recurrence rates following RFA are described. The current literature on RFA of hepatic malignancies is reviewed. Results: RFA of hepatic tumors can be performed percutaneously, laparoscopically, or during an open surgical procedure. Incomplete treatment manifest as local recurrence is more common with a percutaneous approach. The morbidity and mortality rates associated with hepatic RFA are low. Local recurrence rates are low if meticulous treatment planning is performed. RFA can be combined safely with partial hepatic resection of large lesions. The long-term survival rates following RFA of primary and metastatic liver tumors have not yet been established. Conclusions: RFA of hepatic malignancies is a safe and promising technique to produce coagulative necrosis of unresectable hepatic malignancies. Experience with this treatment modality is not yet mature enough to establish long-term outcomes.
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paper_title: Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles.

paper_content:

Abstract Due to their unique magnetic properties, excellent biocompatibility as well as multi-purpose biomedical potential (e.g., applications in cancer therapy and general drug delivery), superparamagnetic iron oxide nanoparticles (SPIONs) are attracting increasing attention in both pharmaceutical and industrial communities. The precise control of the physiochemical properties of these magnetic systems is crucial for hyperthermia applications, as the induced heat is highly dependent on these properties. In this review, the limitations and recent advances in the development of superparamagnetic iron oxide nanoparticles for hyperthermia are presented.
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paper_title: Magnetic Particle Imaging Tracers: State-of-the-Art and Future Directions

paper_content:

Magnetic particle imaging (MPI) is an emerging imaging modality with promising applications in diagnostic imaging and guided therapy. The image quality in MPI is strongly dependent on the nature of its iron oxide nanoparticle-based tracers. The selection of potential MPI tracers is currently limited, and the underlying physics of tracer response is not yet fully understood. An in-depth understanding of the magnetic relaxation processes that govern MPI tracers, gained through concerted theoretical and experimental work, is crucial to the development of optimized MPI tracers. Although tailored tracers will lead to improvements in image quality, tailored relaxation may also be exploited for biomedical applications or more flexible image contrast, as in the recent demonstration of color MPI.
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paper_title: Morbidity and quality of life during thermotherapy using magnetic nanoparticles in locally recurrent prostate cancer: Results of a prospective phase I trial

paper_content:

Purpose: To investigate the treatment-related morbidity and quality of life (QoL) during thermotherapy using superparamagnetic nanoparticles in patients with locally recurrent prostate cancer.Materials and Methods: Ten patients with biopsy-proven locally recurrent prostate cancer following primary therapy with curative intent and no detectable metastases were entered on a prospective phase I trial. Endpoints were feasibility, toxicity and QoL. Following intraprostatic injection of a nanoparticle dispersion, six thermal therapy sessions of 60 min duration were delivered at weekly intervals using an alternating magnetic field. National Cancer Institute (NCI) common toxicity criteria (CTC) and the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-PR25 questionnaires were used to evaluate toxicity and QoL, respectively. In addition, prostate specific antigen (PSA) measurements were carried out.Results: Maximum temperatures up to 55°C were achieved in the prostates at 25–30% of...
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paper_title: Nanoparticle-mediated thermal therapy: Evolving strategies for prostate cancer therapy

paper_content:

Purpose: Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles of different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customised gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumours or preferential accumulation in tumours following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia.Conclusions: Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanop...
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paper_title: Physical limits of hyperthermia using magnetite fine particles

paper_content:

Structural and magnetic properties of fine particles of magnetite are investigated with respect to the application for hyperthermia. Magnetic hysteresis losses are measured in dependence on the field amplitude for selected commercial powders and are discussed in terms of grain size and structure of the particles. For ferromagnetic powders as well as for ferrofluids, results of heating experiments within organic gels in a magnetic high frequency field are reported. The heating effect depends strongly on the magnetic properties of the magnetite particles which may vary appreciably for different samples in dependence on the particle size and microstructure. In particular, the transition from ferromagnetic to superparamagnetic behavior causes changes of the loss mechanism, and accordingly, of the heating effect. The maximum attainable heating effect is discussed in terms of common theoretical models. Rise of temperature at the surface of a small heated sample as well as in its immediate neighborhood in the surrounding medium is measured in dependence on time and is compared with solutions of the corresponding heat conductivity problem. Conclusions with respect to clinical applications are given.
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paper_title: Heating magnetic fluid with alternating magnetic field

paper_content:

This study develops analytical relationships and computations of power dissipation in magnetic fluid (ferrofluid) subjected to alternating magnetic field. The dissipation results from the orientational relaxation of particles having thermal fluctuations in a viscous medium.
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paper_title: Accuracy of available methods for quantifying the heat power generation of nanoparticles for magnetic hyperthermia.

paper_content:

In magnetic hyperthermia, characterising the specific functionality of magnetic nanoparticle arrangements is essential to plan the therapies by simulating maximum achievable temperatures. This functionality, i.e. the heat power released upon application of an alternating magnetic field, is quantified by means of the specific absorption rate (SAR), also referred to as specific loss power (SLP). Many research groups are currently involved in the SAR/SLP determination of newly synthesised materials by several methods, either magnetic or calorimetric, some of which are affected by important and unquantifiable uncertainties that may turn measurements into rough estimates. This paper reviews all these methods, discussing in particular sources of uncertainties, as well as their possible minimisation. In general, magnetic methods, although accurate, do not operate in the conditions of magnetic hyperthermia. Calorimetric methods do, but the easiest to implement, the initial-slope method in isoperibol conditions, derives inaccuracies coming from the lack of matching between thermal models, experimental set-ups and measuring conditions, while the most accurate, the pulse-heating method in adiabatic conditions, requires more complex set-ups.
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paper_title: Inductive heating of ferrimagnetic particles and magnetic fluids: Physical evaluation of their potential for hyperthermia

paper_content:

The potential of colloidal subdomain ferrite particle suspensions (SDP) ('magnetic fluids'), exposed to an alternating magnetic field, is evaluated for hyperthermia. Power absorption measurements of different magnetic fluids are presented in comparison to multidomain ferrite particles (MDP). Variations with frequency as well as magnetic field strength have been investigated. The experimental results clearly indicate a definite superiority of even non-optimized magnetic fluids over MDP ferrites regarding their specific absorption rate (SAR). Based on the work of Shliomis et al. (1990) and Hanson (1991), a solid-state physical model is applied to explain the specific properties of magnetic fluids with respect to a possible use in hyperthermia. The experimentally determined SAR data on magnetic fluids are used to estimate the heating capabilities of a magnetic induction heating technique assuming typical human dimensions and tissue parameters. It is considered that for a moderate concentration of 5 mg ferrite per gram tumour (i.e. 0.5% w/w) and clinically acceptable magnetic fields, intratumoral power absorption is comparable to RF heating with local applicators and superior to regional RF heating (by comparison with clinical SAR measurements from regional and local hyperthermia treatments). Owing to the high particle density per volume, inductive heating by magnetic fluids can improve temperature distributions in critical regions. Furthermore, localized application of magnetic fluids in a tumour might be easier and less traumatic than interstitial implantation techniques.
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paper_title: Heating ability of magnetite nanobeads with various sizes for magnetic hyperthermia at 120kHz, a noninvasive frequency

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We synthesized four kinds of magnetite particles having average sizes of 7, 18, 40, and 80nm and investigated their heating ability when they were dispersed in an agar gel and exposed to an ac magnetic field at 120kHz, a noninvasive frequency for anticancer hyperthermia. The particles 18nm in average diameter gave the highest heating ability, though they exhibited narrow hysteresis loops as compared to the particles having average diameters of 40 and 80nm. This indicates that hysteresis loss does not contribute much to the heat rise by the 120kHz ac field, and Neel relaxation is dominantly contributing to the heat rise by the 18nm sized particles. A calculation based on Neel relaxation loss gave a plausible explanation.
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paper_title: Physics of heat generation using magnetic nanoparticles for hyperthermia.

paper_content:

Magnetic nanoparticle hyperthermia and thermal ablation have been actively studied experimentally and theoretically. In this review, we provide a summary of the literature describing the properties of nanometer-scale magnetic materials suspended in biocompatible fluids and their interactions with external magnetic fields. Summarised are the properties and mechanisms understood to be responsible for magnetic heating, and the models developed to understand the behaviour of single-domain magnets exposed to alternating magnetic fields. Linear response theory and its assumptions have provided a useful beginning point; however, its limitations are apparent when nanoparticle heating is measured over a wide range of magnetic fields. Well-developed models (e.g. for magnetisation reversal mechanisms and pseudo-single domain formation) available from other fields of research are explored. Some of the methods described include effects of moment relaxation, anisotropy, nanoparticle and moment rotation mechanisms, interactions and collective behaviour, which have been experimentally identified to be important. Here, we will discuss the implicit assumptions underlying these analytical models and their relevance to experiments. Numerical simulations will be discussed as an alternative to these simple analytical models, including their applicability to experimental data. Finally, guidelines for the design of optimal magnetic nanoparticles will be presented.
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paper_title: Magnetic Nanoparticles for Cancer Therapy

paper_content:

Today, technologies based on magnetic nanoparticles (MNPs) are routinely applied to biological systems with diagnostic or therapeutic purposes. The paradigmatic example is the magnetic resonance imaging (MRI), a technique that uses the magnetic moments of MNPs as a disturbance of the proton resonance to obtain images. Similarly, magnetic fluid hyperthermia (MFH) uses MNPs as heat generators to induce localized cell death. The physical basis of these techniques relies on the interaction with external magnetic fields, and therefore the magnetic moment of the particles has to be maximized for these applications. Targeted drug-delivery based on 'smart' nanoparticles is the next step towards more efficient oncologic therapies, by delivering a minimal dose of drug only to the vicinity of the target. Current improvements in this fields relay on a) particle functionalization with specific ligands for targeting cell membrane recep- tors and b) loading MNPs onto cells (e.g., dendritic cells, T-cells, macrophages) having an active role in tumor grow. Here we review the current state of research on applications of magnetic carriers for cancer therapy, discussing the advances and drawbacks of both passive and targeted delivery of MNPs. The most promising strategies for targeted delivery of MNPs are analyzed, evaluating the expected im- pact on clinical MRI and MFH protocols.
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paper_title: Impact of magnetic field parameters and iron oxide nanoparticle properties on heat generation for use in magnetic hyperthermia.

paper_content:

Abstract Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe 3 O 4 ) and maghemite (γ-Fe 2 O 3 ) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1–47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo .
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paper_title: Simple models for dynamic hysteresis loop calculations of magnetic single-domain nanoparticles: Application to magnetic hyperthermia optimization

paper_content:

To optimize the heating properties of magnetic nanoparticles (MNPs) in magnetic hyperthermia applications, it is necessary to calculate the area of their hysteresis loops in an alternating magnetic field. The separation between “relaxation losses” and “hysteresis losses” presented in several articles is artificial and criticized here. The three types of theories suitable for describing hysteresis loops of MNPs are presented and compared to numerical simulations: equilibrium functions, Stoner–Wohlfarth model based theories (SWMBTs), and a linear response theory (LRT) using the Neel–Brown relaxation time. The configuration where the easy axis of the MNPs is aligned with respect to the magnetic field and the configuration of a random orientation of the easy axis are both studied. Suitable formulas to calculate the hysteresis areas of major cycles are deduced from SWMBTs and from numerical simulations; the domain of validity of the analytical formula is explicitly studied. In the case of minor cycles, the hys...
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paper_title: Magnetic particle hyperthermia?a promising tumour therapy?

paper_content:

We present a critical review of the state of the art of magnetic particle hyperthermia (MPH) as a minimal invasive tumour therapy. Magnetic principles of heating mechanisms are discussed with respect to the optimum choice of nanoparticle properties. In particular, the relation between superparamagnetic and ferrimagnetic single domain nanoparticles is clarified in order to choose the appropriate particle size distribution and the role of particle mobility for the relaxation path is discussed. Knowledge of the effect of particle properties for achieving high specific heating power provides necessary guidelines for development of nanoparticles tailored for tumour therapy. Nanoscale heat transfer processes are discussed with respect to the achievable temperature increase in cancer cells. The need to realize a well-controlled temperature distribution in tumour tissue represents the most serious problem of MPH, at present. Visionary concepts of particle administration, in particular by means of antibody targeting, are far from clinical practice, yet. On the basis of current knowledge of treating cancer by thermal damaging, this article elucidates possibilities, prospects, and challenges for establishment of MPH as a standard medical procedure.
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paper_title: Magnetic particle hyperthermia : nanoparticle magnetism and materials development for cancer therapy

paper_content:

Loss processes in magnetic nanoparticles are discussed with respect to optimization of the specific loss power (SLP) for application in tumour hyperthermia. Several types of magnetic iron oxide nanoparticles representative for different preparation methods (wet chemical precipitation, grinding, bacterial synthesis, magnetic size fractionation) are the subject of a comparative study of structural and magnetic properties. Since the specific loss power useful for hyperthermia is restricted by serious limitations of the alternating field amplitude and frequency, the effects of the latter are investigated experimentally in detail. The dependence of the SLP on the mean particle size is studied over a broad size range from superparamagnetic up to multidomain particles, and guidelines for achieving large SLP under the constraints valid for the field parameters are derived. Particles with the mean size of 18 nm having a narrow size distribution proved particularly useful. In particular, very high heating power may be delivered by bacterial magnetosomes, the best sample of which showed nearly 1 kW g −1 at 410 kHz and 10 kA m −1 . This value may even be exceeded by metallic magnetic particles, as indicated by measurements on cobalt particles.
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paper_title: Maghemite nanoparticles with very high AC-losses for application in RF-magnetic hyperthermia

paper_content:

Maghemite nanoparticles covalently coated with polyethylene glycol are investigated with respect to different loss processes in magnetic AC-fields. Transmission electron microscopy reveals a narrow size distribution which may be well approximated by a normal distribution (mean diameter 15.3 nm and distribution width 4.9 nm). Aqueous ferrofluids were characterised by DC-magnetometry, by measuring susceptibility spectra for a frequency range 20 Hz to 1 MHz and by calorimetric measurements of specific loss power (SLP) at 330 and 410 kHz for field amplitudes up to 11.7 kA/m. Extremely high values of SLP in the order of 600 W/g result for 400 kHz and 11 kA/m. In addition to liquid ferrofluids measurements were performed with suspensions in gel in order to elucidate the role of Brownian relaxation. The measured susceptibility spectra may be well reproduced by a model using a superposition of Neel and Brown loss processes under consideration of the observed narrow normal size distribution. In this way the observed very high specific heating power may be well understood. Results are discussed with respect to further optimisation of SLP for medical as well as technical RF-heating applications.
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paper_title: Evaluation of iron-cobalt/ferrite core-shell nanoparticles for cancer thermotherapy

paper_content:

Magnetic nanoparticles (MNPs) offer promise for local hyperthermia or thermoablative cancer therapy. Magnetic hyperthermia uses MNPs to heat cancerous regions in an rf field. Metallic MNPs have larger magnetic moments than iron oxides, allowing similar heating at lower concentrations. By tuning the magnetic anisotropy in alloys, the heating rate at a particular particle size can be optimized. Fe–Co core-shell MNPs have protective CoFe2O4 shell which prevents oxidation. The oxide coating also aids in functionalization and improves biocompatibility of the MNPs. We predict the specific loss power (SLP) for FeCo (SLP ∼450W∕g) at biocompatible fields to be significantly larger in comparision to oxide materials. The anisotropy of Fe-Co MNPs may be tuned by composition and/or shape variation to achieve the maximum SLP at a desired particle size.
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paper_title: The effects of magnetic nanoparticle properties on magnetic fluid hyperthermia

paper_content:

Magnetic fluid hyperthermia (MFH) is a noninvasive treatment that destroys cancer cells by heating a ferrofluid-impregnated malignant tissue with an ac magnetic field while causing minimal damage to the surrounding healthy tissue. The strength of the magnetic field must be sufficient to induce hyperthermia but it is also limited by the human ability to safely withstand it. The ferrofluid material used for hyperthermia should be one that is readily produced and is nontoxic while providing sufficient heating. We examine six materials that have been considered as candidates for MFH use. Examining the heating produced by nanoparticles of these materials, barium-ferrite and cobalt-ferrite are unable to produce sufficient MFH heating, that from iron-cobalt occurs at a far too rapid rate to be safe, while fcc iron-platinum, magnetite, and maghemite are all capable of producing stable controlled heating. We simulate the heating of ferrofluid-loaded tumors containing nanoparticles of the latter three materials to ...
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paper_title: Theoretical assessment of FePt nanoparticles as heating elements for magnetic hyperthermia

paper_content:

FePt magnetic nanoparticles (MNPs) are expected to be a high-performance nanoheater for magnetic hyperthermia because of their high Curie temperature, high saturation magnetization, and high chemical stability. Here, we present a theoretical performance assessment of chemically disordered fcc-phase FePt MNPs. We calculate heat generation and heat transfer in the tissue when an MNP-loaded tumor is placed on an external alternating magnetic field. For comparison, we estimate the performances of magnetite, maghemite, FeCo, and L10-phase FePt MNPs. We find that an fcc FePt MNP has a superior ability in magnetic hyperthermia
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paper_title: Nanomedicine: Magnetic Nanoparticles and their Biomedical Applications

paper_content:

During this past decade, science and engineering have seen a rapid increase in interest for nanoscale materials with dimensions less than 100 nm, which lie in the intermediate state between atoms and bulk (solid) materials. Their attributes are significantly altered relative to the corresponding bulk materials as they exhibit size dependent behavior such as quantum size effects (depending on bulk Bohr radius), optical absorption and emission, coulomb staircase behavior (electrical transport), superparamagnetism and various unique properties. They are active components of ferrofluids, recording tape, flexible disk recording media along with potential future applications in spintronics: a new paradigm of electronics utilizing intrinsic charge and spin of electrons for ultra-high-density data storage and quantum computing. They are used in a gamut of biomedical applications: bioseparation of biological entities, therapeutic drugs and gene delivery, radiofrequency-induced destruction of cells and tumors (hyperthermia), and contrast-enhancement agents for magnetic resonance imaging (MRI). The magnetic nanoparticles have optimizable, controllable sizes enabling their comparison to cells (10-100 μm), viruses (20-250 nm), proteins (3-50 nm), and genes (10-100 nm). Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) provide necessary characterization methods that enable accurate structural and functional analysis of interaction of the biofunctional particles with the target bioentities. The goal of the present discussion is to provide a broad review of magnetic nanoparticle research with a special focus on the synthesis, functionalization and medical applications of these particles, which have been carried out during the past decade, and to examine several prospective directions.
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paper_title: The heating effect of magnetic fluids in an alternating magnetic field

paper_content:

The heating mechanism and influencing factors of magnetite particles in a 63 kHz alternating magnetic field and 7 kA/m were studied. The results from in vivo heating experiments suggest that magnetite particles can generate enough energy to heat tumor tissue and perform effective hyperthermia. A novel model for predicting power losses has been proposed.
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paper_title: Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment

paper_content:

Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-soluble IONCs prepared by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were determined as a function of frequency and magnetic field applied, also spanning technical conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an average diameter of 19 ± 3 nm had significant SAR values in clinical conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kAm–1, which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 °C was reached after 1 h of treatment.
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paper_title: Enhancing cancer therapeutics using size-optimized magnetic fluid hyperthermia

paper_content:

Magnetic fluid hyperthermia (MFH) employs heat dissipation from magnetic nanoparticles to elicit a therapeutic outcome in tumor sites, which results in either cell death (>42 °C) or damage (<42 °C) depending on the localized rise in temperature. We investigated the therapeutic effect of MFH in immortalized T lymphocyte (Jurkat) cells using monodisperse magnetite (Fe3O4) nanoparticles (MNPs) synthesized in organic solvents and subsequently transferred to aqueous phase using a biocompatible amphiphilic polymer. Monodisperse MNPs, ∼16 nm diameter, show maximum heating efficiency, or specific loss power (watts/g Fe3O4) in a 373 kHz alternating magnetic field. Our in vitro results, for 15 min of heating, show that only 40% of cells survive for a relatively low dose (490 μg Fe/ml) of these size-optimized MNPs, compared to 80% and 90% survival fraction for 12 and 13 nm MNPs at 600 μg Fe/ml. The significant decrease in cell viability due to MNP-induced hyperthermia from only size-optimized nanoparticles demonstrates the central idea of tailoring size for a specific frequency in order to intrinsically improve the therapeutic potency of MFH by optimizing both dose and time of application.
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paper_title: Simulation and experimental studies on magnetic hyperthermia with use of superparamagnetic iron oxide nanoparticles.

paper_content:

Our purpose of this study was to present simulation and experimental studies on magnetic hyperthermia (MH) with use of an alternating magnetic field (AMF) and superparamagnetic iron oxide nanoparticles (Resovist®). In the simulation studies, the energy dissipation (P) and temperature rise rate (∆T/∆t) were computed under various conditions by use of the probability density function of the particle size distribution based on a log-normal distribution. P and ∆T/∆t and their dependence on the frequency of the AMF (f) largely depended on the particle size of Resovist®. P and ∆T/∆t reached maximum at a diameter of ~24 nm, and were proportional to the amplitude of the AMF (H (0)) raised to a power of ~2.0. In the experimental studies, we made a device for generating an AMF, and measured the temperature rise under various concentrations of Resovist®, H (0), and f. The temperature rise at 10 min after the start of heating was linearly proportional to the concentration of Resovist®, and proportional to H (0) raised to a power of ~2.4, which was slightly greater than that expected from the simulation studies. There was a tendency for the temperature rise to saturate with increasing f. In conclusion, this study will be useful for investigating the feasibility of MH with Resovist® and optimizing the parameters for it.
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paper_title: The heating effect of magnetic fluids in an alternating magnetic field

paper_content:

The heating mechanism and influencing factors of magnetite particles in a 63 kHz alternating magnetic field and 7 kA/m were studied. The results from in vivo heating experiments suggest that magnetite particles can generate enough energy to heat tumor tissue and perform effective hyperthermia. A novel model for predicting power losses has been proposed.
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paper_title: Size dependence of specific power absorption of Fe3O4 particles in AC magnetic field

paper_content:

Abstract The specific absorption rate (SAR) values of aqueous suspensions of magnetite particles with different diameters varying from 7.5 to 416 nm were investigated by measuring the time-dependent temperature curves in an external alternating magnetic field (80 kHz, 32.5 kA/m). Results indicate that the SAR values of magnetite particles are strongly size dependent. For magnetite particles larger than 46 nm, the SAR values increase as the particle size decreases where hysteresis loss is the main contribution mechanism. For magnetite particles of 7.5 and 13 nm which are superparamagnetic, hysteresis loss decreases to zero and, instead, relaxation losses (Neel loss and Brownian rotation loss) dominate, but Brown and Neel relaxation losses of the two samples are all relatively small in the applied frequency of 80 kHz.
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paper_title: Simple models for dynamic hysteresis loop calculations of magnetic single-domain nanoparticles: Application to magnetic hyperthermia optimization

paper_content:

To optimize the heating properties of magnetic nanoparticles (MNPs) in magnetic hyperthermia applications, it is necessary to calculate the area of their hysteresis loops in an alternating magnetic field. The separation between “relaxation losses” and “hysteresis losses” presented in several articles is artificial and criticized here. The three types of theories suitable for describing hysteresis loops of MNPs are presented and compared to numerical simulations: equilibrium functions, Stoner–Wohlfarth model based theories (SWMBTs), and a linear response theory (LRT) using the Neel–Brown relaxation time. The configuration where the easy axis of the MNPs is aligned with respect to the magnetic field and the configuration of a random orientation of the easy axis are both studied. Suitable formulas to calculate the hysteresis areas of major cycles are deduced from SWMBTs and from numerical simulations; the domain of validity of the analytical formula is explicitly studied. In the case of minor cycles, the hys...
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paper_title: Evaluation of iron-cobalt/ferrite core-shell nanoparticles for cancer thermotherapy

paper_content:

Magnetic nanoparticles (MNPs) offer promise for local hyperthermia or thermoablative cancer therapy. Magnetic hyperthermia uses MNPs to heat cancerous regions in an rf field. Metallic MNPs have larger magnetic moments than iron oxides, allowing similar heating at lower concentrations. By tuning the magnetic anisotropy in alloys, the heating rate at a particular particle size can be optimized. Fe–Co core-shell MNPs have protective CoFe2O4 shell which prevents oxidation. The oxide coating also aids in functionalization and improves biocompatibility of the MNPs. We predict the specific loss power (SLP) for FeCo (SLP ∼450W∕g) at biocompatible fields to be significantly larger in comparision to oxide materials. The anisotropy of Fe-Co MNPs may be tuned by composition and/or shape variation to achieve the maximum SLP at a desired particle size.
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paper_title: Simple models for dynamic hysteresis loop calculations of magnetic single-domain nanoparticles: Application to magnetic hyperthermia optimization

paper_content:

To optimize the heating properties of magnetic nanoparticles (MNPs) in magnetic hyperthermia applications, it is necessary to calculate the area of their hysteresis loops in an alternating magnetic field. The separation between “relaxation losses” and “hysteresis losses” presented in several articles is artificial and criticized here. The three types of theories suitable for describing hysteresis loops of MNPs are presented and compared to numerical simulations: equilibrium functions, Stoner–Wohlfarth model based theories (SWMBTs), and a linear response theory (LRT) using the Neel–Brown relaxation time. The configuration where the easy axis of the MNPs is aligned with respect to the magnetic field and the configuration of a random orientation of the easy axis are both studied. Suitable formulas to calculate the hysteresis areas of major cycles are deduced from SWMBTs and from numerical simulations; the domain of validity of the analytical formula is explicitly studied. In the case of minor cycles, the hys...
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paper_title: Magnetic Properties of Magnetic Nanoparticles for Efficient Hyperthermia

paper_content:

Localized magnetic hyperthermia using magnetic nanoparticles (MNPs) under the application of small magnetic fields is a promising tool for treating small or deep-seated tumors. For this method to be applicable, the amount of MNPs used should be minimized. Hence, it is essential to enhance the power dissipation or heating efficiency of MNPs. Several factors influence the heating efficiency of MNPs, such as the amplitude and frequency of the applied magnetic field and the structural and magnetic properties of MNPs. We discuss some of the physics principles for effective heating of MNPs focusing on the role of surface anisotropy, interface exchange anisotropy and dipolar interactions. Basic magnetic properties of MNPs such as their superparamagnetic behavior, are briefly reviewed. The influence of temperature on anisotropy and magnetization of MNPs is discussed. Recent development in self-regulated hyperthermia is briefly discussed. Some physical and practical limitations of using MNPs in magnetic hyperthermia are also briefly discussed.
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paper_title: Spin pinning at ferrite‐organic interfaces

paper_content:

We have previously reported a drastic moment decrease in NiFe2O4 fine particles (∠100A dia.) coated with an organic surfactant such as oleic acid. Removal of the organic coating restored the moment of the particles. Continued investigation has demonstrated that the apparent moment decrease is due to strong pinning of the spins of those ferrite cations that are bonded to the organic molecules. The evidence for this model includes: (1) UNcoated NiFe2O4 particles, prepared in an otherwise identical fashion and with the same size distribution showed no decrease in moment. This observation eliminates the possibility that defects or abnormal surface morphology are responsible for the decreased moment. (2) Low temperature Mossbauer measurements in zero field of coated and uncoated particles showed identical spectra associated with ordered fine particle NiFe2O4. (3) Mossbauer data taken on coated particles in a field of 68.6 kOe applied along the direction of γ‐ray emission showed only a small decrease of the Pm=...
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paper_title: Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs.

paper_content:

Abstract Magnetic hyperthermia mediated by magnetic nanomaterials is one promising antitumoral nanotherapy, particularly for its ability to remotely destroy deep tumors. More and more new nanomaterials are being developed for this purpose, with improved heat-generating properties in solution. However, although the ultimate target of these treatments is the tumor cell, the heating efficiency, and the underlying mechanisms, are rarely studied in the cellular environment. Here we attempt to fill this gap by making systematic measurements of both hyperthermia and magnetism in controlled cell environments, using a wide range of nanomaterials. In particular, we report a systematic fall in the heating efficiency for nanomaterials associated with tumour cells. Real-time measurements showed that this loss of heat-generating power occurred very rapidly, within a matter of minutes. The fall in heating correlated with the magnetic characterization of the samples, demonstrating a complete inhibition of the Brownian relaxation in cellular conditions.
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paper_title: Simulating physiological conditions to evaluate nanoparticles for magnetic fluid hyperthermia (MFH) therapy applications

paper_content:

Abstract Magnetite nanoparticles with high self-heating capacity and low toxicity characteristics are a promising candidate for cancer hyperthermia treatment. In order to achieve minimum dosage to a patient, magnetic nanoparticles with high heating capacity are needed. In addition, the influence of physiological factors on the heat capacity of a material should be investigated in order to determine the feasibility. In this study, magnetite nanoparticles coated with lauric acid were prepared by co-precipitation of Fe3+:Fe2+ in a ratio of 2:1, 5:3, 3:2, and 4:3, and the pH was controlled using NaOH. Structural and magnetization characterization by means of X-ray diffractometry (XRD) and a superconducting quantum interference device (SQUID) revealed that the main species was Fe3O4 and further showed that most of the nanoparticles exhibited superparamagnetic properties. All of the magnetic nanoparticles showed a specific absorption rate (SAR) increase that was linear with the magnetic field strength and frequency of the alternating magnetic field. Among all, the magnetic nanoparticles prepared in a 3:2 ratio showed the highest SAR. To further test the influence of physiological factors on the 3:2 ratio magnetic nanoparticles, we simulated the environment with protein (bovine serum albumin, BSA), blood sugar (dextrose), electrolytes (commercial norm-saline) and viscosity (glycerol) to examine the heating capacity under these conditions. Our results showed that the SAR value was unaffected by the protein and blood sugar environments. On the other hand, the SAR value was significantly reduced in the electrolyte environment, due to precipitation and aggregation with sodium ions. For the simulated viscous environment with glycerol, the result showed that the SAR values reduced with increasing glycerol concentration. We have further tested the heating capacity contribution from the Neel mechanism by trapping the magnetic nanoparticles in a solid form of polydimethylsiloxane (PDMS) to eliminate the heating pathway due to a Brownian motion. We measured the heating capability and determined that 47% of the total heat generated by the magnetic nanoparticles was from the Neel mechanism contribution. For evaluating magnetic nanoparticles, this method provides a fast and low cost method for determining qualitative and quantitative information measurement for the effect of physiological interference and could greatly reduce the cost and time by in vitro or animal test.
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paper_title: In vitro characterization of movement, heating and visualization of magnetic nanoparticles for biomedical applications

paper_content:

Magnetic nanoparticles can be used for a variety of biomedical applications. They can be used in the targeted delivery of therapeutic agents in vivo, in the hyperthermic treatment of cancers, in magnetic resonance (MR) imaging as contrast agents and in the biomagnetic separations of biomolecules. In this study, a characterization of the movement and heating of three different types of magnetic nanoparticles in physiological systems in vitro is made in a known external magnetic field and alternating field respectively. Infra-red (IR) imaging and MR imaging were used to visualize these nanoparticles in vitro. A strong dependence on the size and the suspending medium is observed on the movement and heating of these nanoparticles. First, two of the particles (mean diameter d = 10 nm, uncoated Fe3O4 and d = 2.8 µm, polystyrene coated Fe3O4+γ-Fe2O3) did not move while only a dextran coated nanoparticle (d = 50 nm, γ-Fe2O3) moved in type 1 collagen used as an in vitro model system. It is also observed that the time taken by a collection of these nanoparticles to move even a smaller distance (5 mm) in collagen (~100 min) is almost ten times higher when compared to the time taken to move twice the distance (10 mm) in glycerol (~10 min) under the same external field. Second, the amount of temperature rise increases with the concentration of nanoparticles regardless of the microenvironments in the heating studies. However, the amount of heating in collagen (maximum change in temperature ΔTmax~9 °C at 1.9 mg Fe ml−1 and 19 °C at 3.7 mg Fe ml−1) is significantly less than that in water (ΔTmax~15 °C at 1.9 mg Fe ml−1 and 33 °C at 3.7 mg Fe ml−1) and glycerol (ΔTmax~13.5 °C at 1.9 mg Fe ml−1 and 30 °C at 3.7 mg Fe ml−1). Further, IR imaging provides at least a ten times improvement in the range of imaging magnetic nanoparticles, whereby a concentration of (0–4 mg Fe ml−1) could bevisualized as compared to (0–0.4 mg Fe ml−1) by MR imaging. Based on these in vitro studies, important issues and parameters that require further understanding and characterization of these nanoparticles in vivo are discussed.
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paper_title: Magnetic nanoparticles for interstitial thermotherapy - : feasibility, tolerance and achieved temperatures

paper_content:

Background: The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH® 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique.Material and methods: Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transr...
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paper_title: Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment

paper_content:

Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-soluble IONCs prepared by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were determined as a function of frequency and magnetic field applied, also spanning technical conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an average diameter of 19 ± 3 nm had significant SAR values in clinical conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kAm–1, which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 °C was reached after 1 h of treatment.
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paper_title: Design Maps for the Hyperthermic Treatment of Tumors with Superparamagnetic Nanoparticles

paper_content:

A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase ΔT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m(-1); and concentration cMNP varying from 0.02 to 3.5 mg ml(-1). At high frequency field (∼30 MHz), non specific heating dominates and ΔT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the ΔT of the medium grows linearly with cMNP , whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H(2) . Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42°C) and thermal ablation (Ttissue >50°C) are derived in terms of cMNP , operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration - systemic versus intratumor injection - depending on the magnetic and biodistribution properties of the nanoparticles.
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paper_title: Numerical FEM Models for the Planning of Magnetic Induction Hyperthermia Treatments With Nanoparticles

paper_content:

A numerical FEM model of a magnetic fluid hyperthermia (MFH) treatment on an hepatocellular carcinoma (HCC) metastasis has been simulated. Starting from actual CT images of the patient, a 3-D geometry of the anatomical district has been reconstructed and a coupled electromagnetic and thermal transient analysis has been performed, in order to predict the temperature distribution during the treatment. The in vivo effect of blood perfusion has also been implemented through the Pennes's model. Various simulations have been carried out, based on different particle sizes and concentrations, as well as different exciting field intensities.
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paper_title: Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment

paper_content:

Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-soluble IONCs prepared by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were determined as a function of frequency and magnetic field applied, also spanning technical conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an average diameter of 19 ± 3 nm had significant SAR values in clinical conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kAm–1, which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 °C was reached after 1 h of treatment.
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paper_title: Design Maps for the Hyperthermic Treatment of Tumors with Superparamagnetic Nanoparticles

paper_content:

A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase ΔT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m(-1); and concentration cMNP varying from 0.02 to 3.5 mg ml(-1). At high frequency field (∼30 MHz), non specific heating dominates and ΔT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the ΔT of the medium grows linearly with cMNP , whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H(2) . Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42°C) and thermal ablation (Ttissue >50°C) are derived in terms of cMNP , operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration - systemic versus intratumor injection - depending on the magnetic and biodistribution properties of the nanoparticles.
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paper_title: Usable Frequencies in Hyperthermia with Thermal Seeds

paper_content:

Temperature distributions are computed for tissue models assumed to be heated by constant power seeds, and from that, the heating power which the implants have to produce to achieve clinically acceptable temperatures in the tumor are obtained. Calculations of the heat produced by thermal seeds exposed to an electromagnetic induction field showed it to be strongly dependent on the permeability of the material, on the field frequency, on the seed diameter, and on the orientation of the implants with respect to the field. It is recommended that, other parameters permitting, the implants be oriented parallel to the induction field and that the field frequency be approximately 200 kHz or lower. Under these conditions, implants with diameters as small as 0.25 mm produce sufflcient heat for any clinical application without undue heating by eddy currents flowing within the patient. The use of frequencies above the recommended range puts certain restrictions on the implant geometry and on the magnetic properties of their material. Needles oriented perpendicular to the field produce enough heat to reach therapeutic temperatures only within a narrow range of parameters.
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paper_title: Numerical assessment of a criterion for the optimal choice of the operative conditions in magnetic nanoparticle hyperthermia on a realistic model of the human head.

paper_content:

PURPOSE ::: This paper presents a numerical study aiming at assessing the effectiveness of a recently proposed optimisation criterion for determining the optimal operative conditions in magnetic nanoparticle hyperthermia applied to the clinically relevant case of brain tumours. ::: ::: ::: MATERIALS AND METHODS ::: The study is carried out using the Zubal numerical phantom, and performing electromagnetic-thermal co-simulations. The Pennes model is used for thermal balance; the dissipation models for the magnetic nanoparticles are those available in the literature. The results concerning the optimal therapeutic concentration of nanoparticles, obtained through the analysis, are validated using experimental data on the specific absorption rate of iron oxide nanoparticles, available in the literature. ::: ::: ::: RESULTS ::: The numerical estimates obtained by applying the criterion to the treatment of brain tumours shows that the acceptable values for the product between the magnetic field amplitude and frequency may be two to four times larger than the safety threshold of 4.85 × 10(8)A/m/s usually considered. This would allow the reduction of the dosage of nanoparticles required for an effective treatment. In particular, depending on the tumour depth, concentrations of nanoparticles smaller than 10 mg/mL of tumour may be sufficient for heating tumours smaller than 10 mm above 42 °C. Moreover, the study of the clinical scalability shows that, whatever the tumour position, lesions larger than 15 mm may be successfully treated with concentrations lower than 10 mg/mL. The criterion also allows the prediction of the temperature rise in healthy tissue, thus assuring safe treatment. ::: ::: ::: CONCLUSIONS ::: The criterion can represent a helpful tool for planning and optimising an effective hyperthermia treatment.
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paper_title: Magnetic nanoparticles for interstitial thermotherapy - : feasibility, tolerance and achieved temperatures

paper_content:

Background: The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH® 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique.Material and methods: Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transr...
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paper_title: Design Maps for the Hyperthermic Treatment of Tumors with Superparamagnetic Nanoparticles

paper_content:

A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase ΔT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m(-1); and concentration cMNP varying from 0.02 to 3.5 mg ml(-1). At high frequency field (∼30 MHz), non specific heating dominates and ΔT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the ΔT of the medium grows linearly with cMNP , whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H(2) . Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42°C) and thermal ablation (Ttissue >50°C) are derived in terms of cMNP , operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration - systemic versus intratumor injection - depending on the magnetic and biodistribution properties of the nanoparticles.
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paper_title: Magnetic nanoparticle hyperthermia cancer treatment efficacy dependence on cellular and tissue level particle concentration and particle heating properties

paper_content:

The use of nanotechnology for the treatment of cancer affords the possibility of highly specific tumor targeting and improved treatment efficacy. Iron oxide magnetic nanoparticles (IONPs) have demonstrated success as an ablative mono-therapy and targetable adjuvant therapy. However, the relative therapeutic value of intracellular vs. extracellular IONPs remains unclear. Our research demonstrates that both extracellular and intracellular IONPs generate cytotoxicity when excited by an alternating magnetic field (AMF). While killing individual cells via intracellular IONP heating is an attractive goal, theoretical models and experimental results suggest that this may not be possible due to limitations of cell volume, applied AMF, IONP concentration and specific absorption rate (SAR). The goal of this study was to examine the importance of tumor size (cell number) with respect to IONP concentration. Mouse mammary adenocarcinoma cells were incubated with IONPs, washed, spun into different pellet sizes (0.1, 0.5 and 2 million cells) and exposed to AMF. The level of heating and associated cytotoxicity depended primarily on the number of IONPs /amount Fe per cell pellet volume and the relative volume of the cell pellet. Specifically, larger cell pellets achieved greater relative cytotoxicity due to greater iron amounts, close association and subsequently higher temperatures.
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paper_title: Study of the Optimum Dose of Ferromagnetic Nanoparticles Suitable for Cancer Therapy Using MFH

paper_content:

At present, a successful realization of the magnetic fluid hyperthermia (MFH) therapy is conditioned by some unsolved problems. One of these problems is the choice of the correct particle concentration in order to achieve a defined temperature increase in the tumor tissue. A computer-based model was created using COMSOL: Multiphysics in order to simulate the heat dissipation within the tissue for typical configurations of the tumor position in relation to neighboring blood vessels as well as particle distribution within the tumor. The temperature achieved on the tumor border was investigated taking into account physiological parameters of different types of tissues. Using the correct nanoparticle dosage and considering their specific loss power, it is possible to estimate the efficiency of this therapeutic method. If the tumor shape and position are known by suitable medical imaging techniques (e.g., MRI, CT), simulations like this one could provide data in order to achieve the optimum dose and particle distribution in the tumor.
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paper_title: In vitro characterization of movement, heating and visualization of magnetic nanoparticles for biomedical applications

paper_content:

Magnetic nanoparticles can be used for a variety of biomedical applications. They can be used in the targeted delivery of therapeutic agents in vivo, in the hyperthermic treatment of cancers, in magnetic resonance (MR) imaging as contrast agents and in the biomagnetic separations of biomolecules. In this study, a characterization of the movement and heating of three different types of magnetic nanoparticles in physiological systems in vitro is made in a known external magnetic field and alternating field respectively. Infra-red (IR) imaging and MR imaging were used to visualize these nanoparticles in vitro. A strong dependence on the size and the suspending medium is observed on the movement and heating of these nanoparticles. First, two of the particles (mean diameter d = 10 nm, uncoated Fe3O4 and d = 2.8 µm, polystyrene coated Fe3O4+γ-Fe2O3) did not move while only a dextran coated nanoparticle (d = 50 nm, γ-Fe2O3) moved in type 1 collagen used as an in vitro model system. It is also observed that the time taken by a collection of these nanoparticles to move even a smaller distance (5 mm) in collagen (~100 min) is almost ten times higher when compared to the time taken to move twice the distance (10 mm) in glycerol (~10 min) under the same external field. Second, the amount of temperature rise increases with the concentration of nanoparticles regardless of the microenvironments in the heating studies. However, the amount of heating in collagen (maximum change in temperature ΔTmax~9 °C at 1.9 mg Fe ml−1 and 19 °C at 3.7 mg Fe ml−1) is significantly less than that in water (ΔTmax~15 °C at 1.9 mg Fe ml−1 and 33 °C at 3.7 mg Fe ml−1) and glycerol (ΔTmax~13.5 °C at 1.9 mg Fe ml−1 and 30 °C at 3.7 mg Fe ml−1). Further, IR imaging provides at least a ten times improvement in the range of imaging magnetic nanoparticles, whereby a concentration of (0–4 mg Fe ml−1) could bevisualized as compared to (0–0.4 mg Fe ml−1) by MR imaging. Based on these in vitro studies, important issues and parameters that require further understanding and characterization of these nanoparticles in vivo are discussed.
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paper_title: Heating magnetic fluid with alternating magnetic field

paper_content:

This study develops analytical relationships and computations of power dissipation in magnetic fluid (ferrofluid) subjected to alternating magnetic field. The dissipation results from the orientational relaxation of particles having thermal fluctuations in a viscous medium.
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paper_title: Size-dependant heating rates of iron oxide nanoparticles for magnetic fluid hyperthermia.

paper_content:

Using the thermal decomposition of organometallics method we have synthesized high-quality, iron oxide nanoparticles of tailorable size up to ~15nm and transferred them to a water phase by coating with a biocompatible polymer. The magnetic behavior of these particles was measured and fit to a log-normal distribution using the Chantrell method and their polydispersity was confirmed to be very narrow. By performing calorimetry measurements with these monodisperse particles we have unambiguously demonstrated, for the first time, that at a given frequency, heating rates of superparamagnetic particles are dependent on particle size, in agreement with earlier theoretical predictions.
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paper_title: Monodispersed magnetite nanoparticles optimized for magnetic fluid hyperthermia: Implications in biological systems

paper_content:

Magnetite (Fe3O4) nanoparticles (MNPs) are suitable materials for Magnetic Fluid Hyperthermia (MFH), provided their size is carefully tailored to the applied alternating magnetic field (AMF) frequency. Since aqueous synthesis routes produce polydisperse MNPs that are not tailored for any specific AMF frequency, we have developed a comprehensive protocol for synthesizing highly monodispersed MNPs in organic solvents, specifically tailored for our field conditions (f = 376 kHz, H0 = 13.4 kA/m) and subsequently transferred them to water using a biocompatible amphiphilic polymer. These MNPs (σavg. = 0.175) show truly size-dependent heating rates, indicated by a sharp peak in the specific loss power (SLP, W/g Fe3O4) for 16 nm (diameter) particles. For broader size distributions (σavg. = 0.266), we observe a 30% drop in overall SLP. Furthermore, heating measurements in biological medium [Dulbecco’s modified Eagle medium (DMEM) + 10% fetal bovine serum] show a significant drop for SLP (∼30% reduction in 16 nm MN...
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paper_title: Simple models for dynamic hysteresis loop calculations of magnetic single-domain nanoparticles: Application to magnetic hyperthermia optimization

paper_content:

To optimize the heating properties of magnetic nanoparticles (MNPs) in magnetic hyperthermia applications, it is necessary to calculate the area of their hysteresis loops in an alternating magnetic field. The separation between “relaxation losses” and “hysteresis losses” presented in several articles is artificial and criticized here. The three types of theories suitable for describing hysteresis loops of MNPs are presented and compared to numerical simulations: equilibrium functions, Stoner–Wohlfarth model based theories (SWMBTs), and a linear response theory (LRT) using the Neel–Brown relaxation time. The configuration where the easy axis of the MNPs is aligned with respect to the magnetic field and the configuration of a random orientation of the easy axis are both studied. Suitable formulas to calculate the hysteresis areas of major cycles are deduced from SWMBTs and from numerical simulations; the domain of validity of the analytical formula is explicitly studied. In the case of minor cycles, the hys...
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paper_title: The role of blood flow in hyperthermia.

paper_content:

Abstract In hyperthermia blood flowing through a tissue modifies the temperature distribution produced by the heating technique. The effects of blood flow on temperature distribution during uniform heating of tissues have been calculated using a simple mathematical model, normally employed in the measurement of blood flow by radioisotopes. Blood flow increases the heating time required to produce a certain temperature; it sets a maximum temperature which can be attained by a particular heat input and it produces a pronounced difference in temperature of tissues, with different flows, within the heated volume.
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paper_title: The Energy Conservation Equation for Living Tissue

paper_content:

The widely used bio-heat transfer equation is examined regarding its term describing the thermal effects of blood perfusion. It is demonstrated, both by physical arguments and numerical results, that the description of thermal convection by blood is inconsistent in this equation, and that results are in error by the same order of magnitude as the convective energy transport itself.
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paper_title: Thermal injury kinetics in electrical trauma.

paper_content:

The distribution of electrical current and the resultant Joule heating in tissues of the human upper extremity for a worst-case hand-to-hand high-voltage electrical shock was modelled by solving the Bioheat equation using the finite element method. The model of the upper extremity included skin, fat, skeletal muscle, and bone. The parameter sets for these tissues included specific thermal and electrical properties and their respective tissue blood flow rates. The extent of heat mediated cellular injury was estimated by using a damage rate equation based on a single energy barrier chemical reaction model. No cellular injury was assumed to occur for temperatures less than 42 degrees C. This model was solved for the duration of Joule heating required to produce membrane damage in cells, termed the lethal time (of contact) for injury. LT's were determined for contact voltages ranging from 5 to 20 kV. For a 10,000 volt electrical shock LT's for skeletal muscle are predicted to be: 0.5 second in the distal forearm, 1.1 second in the mid-forearm, 1.2 second in the proximal elbow, and 2.0 seconds in the mid-arm. This analysis of the electrical shock provides useful insight into the mechanisms of resultant tissue damage and provides important performance guidelines for the development of safety devices.
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paper_title: Magnetic Fluid Hyperthermia Modeling Based on Phantom Measurements and Realistic Breast Model

paper_content:

Magnetic fluid hyperthermia (MFH) is a minimally invasive procedure that destroys cancer cells. It is based on a superparamagnetic heat phenomenon and consists in feeding a ferrofluid into a tumor, and then applying an external electromagnetic field, which leads to apoptosis. The strength of the magnetic field, optimal dose of the ferrofluid, the volume of the tumor and the safety standards have to be taken into consideration when MFH treatment is planned. In this study, we have presented the novel complementary investigation based both on the experiments and numerical methodology connected with female breast cancer. We have conducted experiments on simplified female breast phantoms with numerical analysis and then we transferred the results on an anatomically-like breast model.
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paper_title: A New Simplified Bioheat Equation for the Effect of Blood Flow on Local Average Tissue Temperature

paper_content:

A new simplified three-dimensional bioheat equation is derived to describe the effect of blood flow on blood-tissue heat transfer. In two recent theoretical and experimental studies [1, 2] the authors have demonstrated that the so-called isotropic blood perfusion term in the existing bioheat equation is negligible because of the microvascular organization, and that the primary mechanism for blood-tissue energy exchange is incomplete countercurrent exchange in the thermally significant microvessels. The new theory to describe this basic mechanism shows that the vascularization of tissue causes it to behave as an anisotropic heat transfer medium. A remarkably simple expression is derived for the tensor conductivity of the tissue as a function of the local vascular geometry and flow velocity in the thermally significant countercurrent vessels. It is also shown that directed as opposed to isotropic blood perfusion between the countercurrent vessels can have a significant influence on heat transfer in regions where the countercurrent vessels are under 70-micron diameter. The new bioheat equation also describes this mechanism.
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paper_title: Theory and experiment for the effect of vascular microstructure on surface tissue heat transfer--Part I: Anatomical foundation and model conceptualization.

paper_content:

A new theoretical model supported by ultrastructural studies and high-spatial resolution temperature measurements is presented for surface tissue heat transfer in a two-part study. In this first paper, vascular casts of the rabbit thigh prepared by the tissue clearance method were serially sectioned parallel to the skin surface to determine the detailed variation of the vascular geometry as a function of tissue depth. Simple quantitative models of the basic vascular structures observed were then analyzed in terms of their characteristic thermal relaxation lengths and a new three-layer conceptual model proposed for surface tissue heat transfer. Fine wire temperature measurements with an 80-micron average diameter thermocouple junction and spatial increments of 20 micrometers between measurement sites have shown for the first time the detailed temperature fluctuations in the microvasculature and have confirmed the fundamental assumptions of the proposed three-layer model for the deep tissue, skeletal muscle and cutaneous layers.
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paper_title: Theory and experiment for the effect of vascular microstructure on surface tissue heat transfer--Part II: Model formulation and solution.

paper_content:

In this paper the conceptual three-layer representation of surface tissue heat transfer proposed in Weinbaum, Jiji and Lemons [1], is developed into a detailed quantitative model. This model takes into consideration the variation of the number density, size and flow velocity of the countercurrent arterio-venous vessels as a function of depth from the skin surface, the directionality of blood perfusion in the transverse vessel layer and the superficial shunting of blood to the cutaneous layer. A closed form analytic solution for the boundary value problem coupling the three layers is obtained. This solution is in terms of numerically evaluated integrals describing the detailed vascular geometry, a capillary bleed-off distribution function and parameters describing the shunting of blood to the cutaneous layer. Representative heat transfer results for typical physiological conditions are presented.
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paper_title: Recent developments in modeling heat transfer in blood perfused tissues

paper_content:

Successful hyperthermia treatment of tumors requires understanding the attendant thermal processes in both diseased and healthy tissue. Accordingly, it is essential for developers and users of hyperthermia equipment to predict, measure and interpret correctly the tissue thermal and vascular response to heating. Modeling of heat transfer in living tissues is a means towards this end. Due to the complex morphology of living tissues, such modeling is a difficult task and some simplifying assumptions are needed. Some investigators have recently argued that Pennes' interpretation of the vascular contribution to heat transfer in perfused tissues fails to account for the actual thermal equilibration process between the flowing blood and the surrounding tissue and proposed new models, presumably based on a more realistic anatomy of the perfused tissue. The present review compares and contrasts several of the new bio-heat transfer models, emphasizing the problematics of their experimental validation, in the absence of measuring equipment capable of reliable evaluation of tissue properties and their variations that occur in the spatial scale of blood vessels with diameters less than about 0.2 mm. For the most part, the new models still lack sound experimental grounding, and in view of their inherent complexity, the best practical approach for modeling bio-heat transfer during hyperthermia may still be the Pennes model, providing its use is based on some insights gained from the studies described here. In such cases, these models should yield a more realistic description of tissue locations and/or thermal conditions for which the Pennes model might not apply. >
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paper_title: Is intracellular hyperthermia superior to extracellular hyperthermia in the thermal sense?

paper_content:

More than 20 years ago, it was hypothesized that intracellular hyperthermia is superior to extracellular hyperthermia. It was further hypothesized that even a single biological cell containing magnetic nanoparticles can be treated for hyperthermia by an AC magnetic field, independent of its surrounding cells. Since experimental investigation of the thermal effects of intracellular hyperthermia is not feasible, these hypotheses have been studied theoretically. The current report shows that nano-scale heating effects are negligible. This study further shows that intracellular heat generation is sufficient to create the necessary conditions for hyperthermia only in a large group of cells loaded with nanoparticles, having an overall diameter of at least 1mm. It is argued in this report that there is no reason to believe that intracellular hyperthermia is superior to extracellular hyperthermia in the thermal sense.
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paper_title: Modeling of temperature profile during magnetic thermotherapy for cancer treatment

paper_content:

Magnetic nanoparticles (MNPs) used as heat sources for cancer thermotherapy have received much recent attention. While the mechanism for power dissipation in MNPs in a rf field is well understood, a challenge in moving to clinical trials is an inadequate understanding of the power dissipation in MNP-impregnated systems and the discrepancy between the predicted and observed heating rates in the same. Here we use the Rosensweig [J. Magn. Magn. Mater. 252, 370 (2002)] model for heat generation in a single MNP, considering immediate heating of the MNPs, and the double spherical-shell heat transfer equations developed by Andra et al. [J. Magn. Magn. Mater. 194, 197 (1999)] to model the heat distribution in and around a ferrofluid sample or a tumor impregnated with MNPs. We model the heat generated at the edge of a 2.15 cm spherical sample of FeCo/(Fe,Co)3O4 agglomerates containing 95 vol % MNPs with mean radius of 9 nm, dispersed at 1.5–1.6 vol % in bisphenol F. We match the model against experimental data for...
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paper_title: Transient solution to the bioheat equation and optimization for magnetic fluid hyperthermia treatment

paper_content:

Two finite concentric spherical regions were considered as the tissue model for magnetic fluid hyperthermia treatment. The inner sphere represents the diseased tissue containing magnetic particles that generate heat when an alternating magnetic field is applied. The outer sphere represents the healthy tissue. Blood perfusion effects are included in both the regions. Analytical and numerical solutions of the one-dimensional bioheat transfer equation were obtained with constant and spatially varying heat generation in the inner sphere. The numerical solution was found to be in good agreement with the analytical solution. In an ideal hyperthermia treatment, all the diseased tissues should be selectively heated without affecting any healthy tissue. The present work optimized the magnetic particle concentration in an attempt to achieve the ideal hyperthermia conditions. It was found that, for a fixed amount of magnetic particles, optimizing the magnetic particle distribution in the diseased tissue can signific...
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paper_title: Temperature distribution as function of time around a small spherical heat source of local magnetic hyperthermia

paper_content:

A spherical region containing magnetic particles embedded in extended muscle tissue is taken as model of small breast carcinomas. Using analytically derived equations the spatial temperature distribution is calculated as function of the time for exposing to an alternating magnetic field. In vitro measurements with muscle tissue yielded such an agreement with the calculations that treatment of small tumors in slightly vascularized tissues on the base of mathematical predictions seems now to be more promising than in the past.
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paper_title: Magnetic Fluid Hyperthermia Modeling Based on Phantom Measurements and Realistic Breast Model

paper_content:

Magnetic fluid hyperthermia (MFH) is a minimally invasive procedure that destroys cancer cells. It is based on a superparamagnetic heat phenomenon and consists in feeding a ferrofluid into a tumor, and then applying an external electromagnetic field, which leads to apoptosis. The strength of the magnetic field, optimal dose of the ferrofluid, the volume of the tumor and the safety standards have to be taken into consideration when MFH treatment is planned. In this study, we have presented the novel complementary investigation based both on the experiments and numerical methodology connected with female breast cancer. We have conducted experiments on simplified female breast phantoms with numerical analysis and then we transferred the results on an anatomically-like breast model.
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paper_title: Errors between two- and three-dimensional thermal model predictions of hyperthermia treatments.

paper_content:

A simulation program to study the three-dimensional temperature distributions produced by hyperthermia in anatomically realistic inhomogenous tissue models has been developed using the bioheat transfer equation. The anatomical data for the inhomogeneous tissues of the human body are entered on a digitizing tablet from serial computed tomography (CT) scans. Power deposition patterns from various heating modalities must be calculated independently. The program has been used to comparatively evaluate two- and three-dimensional simulations in a series of parametric calculations based on a simple inhomogeneous tissue model for uniform power deposition. The conclusions are that two-dimensional simulations always lead to significant errors at the ends of tumors (up to tens of degrees). However, they can give valid results for the central region of large tumors, but only with tumor blood perfusions greater than approximately 1 kg/m3/s. These conclusions from the geometrically simple model are substantiated by the results obtained using the full three-dimensional model for actual patient anatomical simulations. In summary, three-dimensional simulations will be necessary for accurate patient treatment planning. The effect of the thermal conductivity, used in the models, on the temperature field has also been studied. The results show that using any thermal conductivity value in the range of 0.4 to 0.6 W/m/degrees C sufficiently characterizes most soft tissues, especially in the presence of high blood perfusion. However, bone (thermal conductivity of 1.16 W/m/degrees C) and fat (thermal conductivity of 0.2 W/m/degrees C) do not fit this generalization and significant errors result if soft tissue values are used.
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paper_title: Study of the Optimum Injection Sites for a Multiple Metastases Region in Cancer Therapy by Using MFH

paper_content:

Metastases represent the final stage in cancer progression. Their early diagnosis and appropriate treatment are very important in order to maintain a high survival prognostic. The interest in MFH (magnetic fluid hyperthermia) and cancer therapy has noticeably increased in the last years. There are still numerous problems that need to be solved before a clinical model may be tested. The goal of this paper is to both quantify the optimum dose of magnetic material and optimize injection sites in order to achieve a therapeutic temperature of 42degC that may induce apoptosis in tumor cells. A successful realization of this therapy implies a heating zone of at least 2 mm around the tumor. finite element method (FEM) simulations of spherical metastases in liver and breast tissues near a blood vessel were performed using COMSOL multiphysics (heat transfer module) in order to simulate the temperature field produced by ferromagnetic nanoparticles within the tumor and healthy tissues. A systematical variation of tumor diameter and particle dosage was performed for every physical parameter for the tumor tissues mentioned above (e.g., tissue density, tumor/tissue perfusion rate) in order to understand the interdependence of these parameters and their effects on hyperthermia therapy.
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paper_title: Modeling of temperature profile during magnetic thermotherapy for cancer treatment

paper_content:

Magnetic nanoparticles (MNPs) used as heat sources for cancer thermotherapy have received much recent attention. While the mechanism for power dissipation in MNPs in a rf field is well understood, a challenge in moving to clinical trials is an inadequate understanding of the power dissipation in MNP-impregnated systems and the discrepancy between the predicted and observed heating rates in the same. Here we use the Rosensweig [J. Magn. Magn. Mater. 252, 370 (2002)] model for heat generation in a single MNP, considering immediate heating of the MNPs, and the double spherical-shell heat transfer equations developed by Andra et al. [J. Magn. Magn. Mater. 194, 197 (1999)] to model the heat distribution in and around a ferrofluid sample or a tumor impregnated with MNPs. We model the heat generated at the edge of a 2.15 cm spherical sample of FeCo/(Fe,Co)3O4 agglomerates containing 95 vol % MNPs with mean radius of 9 nm, dispersed at 1.5–1.6 vol % in bisphenol F. We match the model against experimental data for...
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paper_title: Transient solution to the bioheat equation and optimization for magnetic fluid hyperthermia treatment

paper_content:

Two finite concentric spherical regions were considered as the tissue model for magnetic fluid hyperthermia treatment. The inner sphere represents the diseased tissue containing magnetic particles that generate heat when an alternating magnetic field is applied. The outer sphere represents the healthy tissue. Blood perfusion effects are included in both the regions. Analytical and numerical solutions of the one-dimensional bioheat transfer equation were obtained with constant and spatially varying heat generation in the inner sphere. The numerical solution was found to be in good agreement with the analytical solution. In an ideal hyperthermia treatment, all the diseased tissues should be selectively heated without affecting any healthy tissue. The present work optimized the magnetic particle concentration in an attempt to achieve the ideal hyperthermia conditions. It was found that, for a fixed amount of magnetic particles, optimizing the magnetic particle distribution in the diseased tissue can signific...
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paper_title: Ferromagnetic Nanoparticles Dose Based on Tumor Size in Magnetic Fluid Hyperthermia Cancer Therapy

paper_content:

The interest in magnetic fluid hyperthermia (MFH) and cancer therapy has noticeably increased in the last years. At present, a successful realization of this interdisciplinary research is hampered by some unsolved problems. One of these problems this paper intended to clarify is how to find an estimate of the appropriate dosage of magnetic nanoparticles that injected into the tumor would help achieve an optimum temperature of 42degC, thus resulting in an increase of the susceptibility for apoptosis in tumor cells. We created a computational model in COMSOL: Multiphysics in order to analyze the heat dissipation within the tumor tissue. By considering various types of tissues with their respective physical and physiological properties (breast, liver, and skin tissues) and also by taking into account the amount of heat generated through the Brownian rotation and the Neel relaxation, it has been studied the tumor border temperature achieved for various concentrations of magnetic nanoparticles in their superparamagnetic behavior. Distinct simulations of a spherical tumor located in a cubical region of a volume of 1.2-3.5 cm3 within the tissue were designed. We performed a systematical variation of tumor diameter and particle dosage for every physical parameter of above mentioned tumor tissues (e.g., tissue density, tumor/tissue perfusion rate). By this systematization we intended to understand the interdependence of these parameters and their effects on hyperthermia therapy.
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paper_title: 3D numerical simulations on GPUs of hyperthermia with nanoparticles by a nonlinear bioheat model

paper_content:

This paper deals with the numerical modeling of hyperthermia treatments by magnetic nanoparticles considering a 3D nonlinear Pennes' bioheat transfer model with a temperature-dependent blood perfusion in order to yield more accurate results. The tissue is modeled by considering skin, fat and muscle layers in addition to the tumor. The FDM in a heterogeneous medium is employed and the resulting system of nonlinear equations in the time domain is solved by a predictor-multicorrector algorithm. Since the execution of the three-dimensional model requires a large amount of time, CUDA is used to speedup it. Experimental results showed that the parallelization with CUDA was very effective in improving performance, yielding gains up to 242 times when compared to the sequential execution time.
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paper_title: Temperature distribution as function of time around a small spherical heat source of local magnetic hyperthermia

paper_content:

A spherical region containing magnetic particles embedded in extended muscle tissue is taken as model of small breast carcinomas. Using analytically derived equations the spatial temperature distribution is calculated as function of the time for exposing to an alternating magnetic field. In vitro measurements with muscle tissue yielded such an agreement with the calculations that treatment of small tumors in slightly vascularized tissues on the base of mathematical predictions seems now to be more promising than in the past.
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paper_title: Numerical simulation of effect of vessel bifurcation on heat transfer in the magnetic fluid hyperthermia

paper_content:

Abstract This research aimed to analyze the mass and heat transfer mechanisms in magnetic fluid hyperthermia (MFH) treatment, revealing the effect of blood flow in a blood vessel bifurcation on the accurate spatial control of the thermal dose. A three-dimensional multiphysical model was developed to obtain the blood flow velocity distribution, concentration distribution of magnetic fluid, and temperature distribution of the treated tumor tissues. The calculated results demonstrate that the structure, size, and position of a bifurcation vessel greatly affect the selection of injection parameters for MFH treatment. The injection parameters considered in this study are the concentration of magnetic fluid, injection volume, arrangement of injections within the targeted tissues, and distance between the injection site and bifurcation. Diffuse injection patterns, large volumes, and low concentrations generally decrease the temperature differences within the tissues. To achieve uniform heating, high injection density and high-concentration magnetic fluids may be applied to the area near the vessel in order to reduce the cooling effect of blood flow. However, a more diffuse injection pattern is advantageous if the distance between the injection site and blood vessel is relatively short for the purpose of eliminating the heating effect of magnetic fluids.
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paper_title: FEM numerical model study of heating in magnetic nanoparticles

paper_content:

Electromagnetic heating of nanoparticles is complicated by the extremely short thermal relaxation time constants and difficulty of coupling sufficient power into the particles to achieve desired temperatures. Magnetic field heating by the hysteresis loop mechanism at frequencies between about 100 and 300 kHz has proven to be an effective mechanism in magnetic nanoparticles. Experiments at 2.45 GHz show that Fe3O4 magnetite nanoparticle dispersions in the range of 1012 to 1013 NP/mL also heat substantially at this frequency. An FEM numerical model study was undertaken to estimate the order of magnitude of volume power density, Qgen (W m-3) required to achieve significant heating in evenly dispersed and aggregated clusters of nanoparticles. The FEM models were computed using Comsol Multiphysics; consequently the models were confined to continuum formulations and did not include film nano-dimension heat transfer effects at the nanoparticle surface. As an example, the models indicate that for a single 36 nm diameter particle at an equivalent dispersion of 1013 NP/mL located within one control volume (1.0 × 10-19 m3) of a capillary vessel a power density in the neighborhood of 1017 (W m-3) is required to achieve a steady state particle temperature of 52 °C - the total power coupled to the particle is 2.44 μW. As a uniformly distributed particle cluster moves farther from the capillary the required power density decreases markedly. Finally, the tendency for particles in vivo to cluster together at separation distances much less than those of the uniform distribution further reduces the required power density.
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paper_title: Modelling mass and heat transfer in nano-based cancer hyperthermia

paper_content:

We derive a sophisticated mathematical model for coupled heat and mass transport in the tumour microenvironment and we apply it to study nanoparticle delivery and hyperthermic treatment of cancer. The model has the unique ability of combining the following features: (i) realistic vasculature; (ii) coupled capillary and interstitial flow; (iii) coupled capillary and interstitial mass transfer applied to nanoparticles; and (iv) coupled capillary and interstitial heat transfer, which are the fundamental mechanisms governing nano-based hyperthermic treatment. This is an improvement with respect to previous modelling approaches, where the effect of blood perfusion on heat transfer is modelled in a spatially averaged form. We analyse the time evolution and the spatial distribution of particles and temperature in a tumour mass treated with superparamagnetic nanoparticles excited by an alternating magnetic field. By means of numerical experiments, we synthesize scaling laws that illustrate how nano-based hyperthermia depends on tumour size and vascularity. In particular, we identify two distinct mechanisms that regulate the distribution of particle and temperature, which are characterized by perfusion and diffusion, respectively.
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paper_title: Errors in temperature measurement by thermocouple probes during ultrasound induced hyperthermia

paper_content:

A major problem in the use of localised hyperthermia for treatment of malignant tumours is to obtain an accurate measurement of the temperature in the tissue being treated. Thermocouple probes have generally been employed for measuring temperature elevation during ultrasound irradiation. However, when small objects such as thermocouples are in an ultrasound field in a medium such as tissue, viscous forces acting between the object and the tissue will cause an additional local rise in temperature (Fry & Fry, 1954a, b; Dunn, 1962; Hynynen et al, 1982). This will produce an error in any measurement of tissue temperature with invasive probes. The magnitude of the temperature elevation resulting from shear viscosity has been measured for 50 μm thermocouples in tumour tissue.
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paper_title: A methodology for determining optimal thermal damage in magnetic nanoparticle hyperthermia cancer treatment

paper_content:

SUMMARY ::: ::: Hyperthermia treatment of tumors uses localized heating to damage cancer cells and can also be utilized to increase the efficacy of other treatment methods such as chemotherapy. Magnetic nanoparticle hyperthermia is one of the least invasive techniques of delivering heat. It is based on injecting magnetic nanoparticles into the tumor and subjecting them to an alternating magnetic field. The technique is aimed at damaging the tumor without affecting the surrounding healthy tissue. In this preliminary study, we consider a simplified model (two concentric spheres that represent the tumor and its surrounding tissues) that employs a numerical solution of the Pennes bioheat equation. The model assumes a Gaussian distribution for the spatial variation of the applied thermal energy and an exponential decay function for the time variation. The objective of the study is to optimize the parameters that control the spatial and the time variation of the thermal energy. The optimization process is performed by formulating a fitness function that rewards damage in the region representing the tumor but penalizes damage in the surrounding tissues. Because of the flatness of this fitness function near the optimum, a genetic algorithm is used as the optimization method for its robust non-gradient-based approach. The overall aim of this work is to propose a methodology that can be used for hyperthermia treatment in a clinical scenario. Copyright © 2011 John Wiley & Sons, Ltd.
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paper_title: Magnetic Resonance Thermometry During Hyperthermia for Human High-Grade Sarcoma

paper_content:

Purpose: To determine the feasibility of measuring temperature noninvasively with magnetic resonance imaging during hyperthermia treatment of human tumors. ::: ::: Methods: The proton chemical shift detected using phase-difference magnetic resonance imaging (MRI) was used to measure temperature in phantoms and human tumors during treatment with hyperthermia. Four adult patients having high-grade primary sarcoma tumors of the lower leg received 5 hyperthermia treatments in the MR scanner using an MRI-compatible radiofrequency heating applicator. Prior to each treatment, an average of 3 fiberoptic temperature probes were invasively placed into the tumor (or phantom). Hyperthermia was applied concurrent with MR thermometry. Following completion of the treatment, regions of interest (ROI) were defined on MR phase images at each temperature probe location, in bone marrow, and in gel standards placed outside the heated region. The median phase difference (compared to pretreatment baseline images) was calculated for each ROI. This phase difference was corrected for phase drift observed in standards and bone marrow. The observed phase difference, with and without corrections, was correlated with the fiberoptic temperature measurements. ::: ::: Results: The phase difference observed with MRI was found to correlate with temperature. Phantom measurements demonstrated a linear regression coefficient of 4.70° phase difference per ° Celsius, with an R2 = 0.998. After human images with artifact were excluded, the linear regression demonstrated a correlation coefficient of 5.5° phase difference per ° Celsius, with an R2 = 0.84. In both phantom and human treatments, temperature measured via corrected phase difference closely tracked measurements obtained with fiberoptic probes during the hyperthermia treatments. ::: ::: Conclusions: Proton chemical shift imaging with current MRI and hyperthermia technology can be used to monitor and control temperature during treatment of large tumors in the distal lower extremity.
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paper_title: The practical use of thermocouples for temperature measurement in clinical hyperthermia

paper_content:

The use of thermocouples as invasive thermometers in clinical hyperthermia is comprehensively and critically reviewed. The ability to construct thermocouple probes as small-bore, multiple junction assemblies is a major reason for their popularity and full constructional details are given. The potential sources of measurement error when using thermocouples both in temperature gradients and in electromagnetic or ultrasonic heating fields are discussed. Emphasis is placed upon simple practical solutions to these problems and a combination of good measurement practice and electrical filtering can reduce errors to an insignificant level. Techniques are suggested for the assessment of thermocouple performance during clinical measurement. With careful use, thermocouples can be reliable and convenient thermometers.
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paper_title: Transient solution to the bioheat equation and optimization for magnetic fluid hyperthermia treatment

paper_content:

Two finite concentric spherical regions were considered as the tissue model for magnetic fluid hyperthermia treatment. The inner sphere represents the diseased tissue containing magnetic particles that generate heat when an alternating magnetic field is applied. The outer sphere represents the healthy tissue. Blood perfusion effects are included in both the regions. Analytical and numerical solutions of the one-dimensional bioheat transfer equation were obtained with constant and spatially varying heat generation in the inner sphere. The numerical solution was found to be in good agreement with the analytical solution. In an ideal hyperthermia treatment, all the diseased tissues should be selectively heated without affecting any healthy tissue. The present work optimized the magnetic particle concentration in an attempt to achieve the ideal hyperthermia conditions. It was found that, for a fixed amount of magnetic particles, optimizing the magnetic particle distribution in the diseased tissue can signific...
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paper_title: Enhancement in treatment planning for magnetic nanoparticle hyperthermia: optimization of the heat absorption pattern.

paper_content:

In clinical applications of magnetic nanoparticle hyperthermia for cancer treatment it is very important to ensure a maximum damage to the tumor while protecting the normal tissue. The resultant heating pattern by the nanoparticle distribution in tumor is closely related to the injection parameters. In this study we develop an optimization algorithm to inversely determine the optimum heating patterns induced by multiple nanoparticle injections in tumor models with irregular geometries. The injection site locations, thermal properties of tumor and tissue, and local blood perfusion rates are used as inputs to the algorithm to determine the optimum parameters of the heat sources for all nanoparticle injection sites. The design objective is to elevate the temperature of at least 90% of the tumor above 43 degrees C, and to ensure only less than 10% of the normal tissue is heated to temperatures of 43 degrees C or higher. The efficiency, flexibility and capability of this approach have been demonstrated in a case study of two tumors with simple or complicated geometry. An extensive experimental database should be developed in the future to relate the optimized heating pattern parameters found in this study to their appropriate nanoparticle concentration, injection amount, and injection rate. We believe that the optimization algorithm developed in this study can be used as a guideline for physicians to design an optimal treatment plan in magnetic nanoparticle hyperthermia.
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Title: Physical Mechanism and Modeling of Heat Generation and Transfer in Magnetic Fluid Hyperthermia through Néelian and Brownian Relaxation: A Review

Section 1: Introduction
Description 1: Provide background on the current cancer treatments, the concept of thermotherapy, types of hyperthermia, and the rationale behind using hyperthermia as a cancer therapy method.

Section 2: Magnetic Fluid Hyperthermia
Description 2: Explain the concept of Magnetic Fluid Hyperthermia (MFH), its advantages over other hyperthermia methods, and its applications in clinical trials.

Section 3: Heat Generation Model Based on Néelian and Brownian Relaxation
Description 3: Detail the mechanisms of heat generation in magnetic nanoparticles via Néelian and Brownian relaxation, including mathematical formulations and the factors influencing these processes.

Section 4: Type of Material
Description 4: Discuss different types of magnetic nanoparticles used in MFH, their properties, and their suitability for clinical applications.

Section 5: Particle Size
Description 5: Describe the influence of particle size on the heating efficiency and treatment outcome of MFH.

Section 6: Anisotropy
Description 6: Discuss the role of magnetic anisotropy in MFH and its influence on the heating properties of nanoparticles.

Section 7: Viscosity
Description 7: Explain the impact of the medium's viscosity on the heat generation in MFH.

Section 8: Magnetic Field Strength
Description 8: Detail the relationship between magnetic field strength and heat generation in MFH.

Section 9: Magnetic Field Frequency
Description 9: Describe the effect of magnetic field frequency on the specific absorption rate (SAR) and the safety considerations for clinical applications.

Section 10: Concentration
Description 10: Discuss the effect of nanoparticles concentration on the heat generation and treatment outcomes in MFH.

Section 11: Polydispersity
Description 11: Explain the impact of particle size distribution (polydispersity) on the heat generation efficiency in MFH.

Section 12: Bioheat Transfer Model for Heat Distribution
Description 12: Provide an overview of various bioheat transfer models used to describe heat distribution in biological tissues during MFH.

Section 13: Analytical Modeling
Description 13: Summarize the development and application of analytical models to predict temperature distribution during MFH.

Section 14: Numerical Modeling
Description 14: Describe the use of numerical methods, such as FEM and FDM, to simulate heat transfer phenomena in MFH.

Section 15: Optimization Model
Description 15: Discuss optimization techniques to maximize therapeutic effects and minimize side effects in MFH.

Section 16: Conclusion
Description 16: Conclude the review by summarizing the potential of MFH as a cancer treatment and the need for further studies to improve simulation accuracy and treatment effectiveness.