Review of recent applications of nanoparticles as sensitizers



Hypoxic cell sensitizers have been used for many years in cancer treatment. The science works every day in the search of the ideal radiation sensitizer in order to increase the success of cancer radiation treatments. The emerging of nanoscience has opened a new world in the cancer treatment. Ideally, nanodelivery systems will allow for more specific targeting on the tumour, thereby improving efficacy and minimizing side effects. The applications of nanoparticles as radiosensitizers concentrates in: delivering the drug to the targeted tissue, releasing the drug at a controlled rate, be a biodegradable drug delivery system, and to be able to escape from degradation processes of the body. Some nanoparticles as gold have the property to absorb the radiation in grater quantities; such property makes gold nanoparticles, a good radiation sensitizer.

Even if it looks like the nanoparticles are the paradigm of radiosensitizers, the uses of nanoparticles imply risks. Chemicals in their nanoparticle form have properties that are completely different from their larger physical forms and may therefore interact differently within biological systems. As a result, it is necessary to assess the risks arising from any nanoparticle that will potentially come in contact with humans, other species or the environment, even if the toxicology of the chemicals that make up the nanoparticle is well known [1].

Some experiments performed in the early part of the last century first established that the absence of oxygen decreases the lethal effects of radiation therapy. Under anaerobic conditions, the radiation dose must be increased by a factor of 2.5 to 3 to achieve the same degree of cytotoxicity that occurs under oxygenated conditions. [2]

Hypoxic conditions are present in tumors and, based on experimental studies, hypoxia appears to be a major cause of treatment failure with radiation therapy and chemotherapy. In animal models, 10% to 20% of tumour cells are generally found to be hypoxic.[3,4] Direct oxygen measurements in human tumours have confirmed tumour hypoxia in glioblastoma multiforme and in carcinomas of the breast, uterine cervix, and head and neck.[3,4] Potential mechanisms of chronic or transient hypoxia include obstruction of blood flow, inadequate or defective (malignant) angiogenesis, and failure of cellular growth control, allowing the cell population to outstrip the capacity of the capillary blood supply. In general, tumour cells are oxygenated up to a distance of about 150 mm from capillaries; beyond this distance, tumour cells become oxygen-depleted and either die or survive in a hypoxic state.[5,6] Since hypoxic cells are substantially more resistant to radiation than are oxygenated cells, even a small hypoxic fraction in a tumour will dominate the overall response to radiation by increasing the probability that some viable tumour cells will survive the treatment. Conversely, few hypoxic cells exist in normal tissues. Therefore, therapies that increase the delivery of oxygen to hypoxic cells are not expected to increase the toxicity of radiation to normal tissues.

Several therapeutic modalities intended to reduce tumour hypoxia in humans have been evaluated in preclinical and clinical trials, and the results of these investigations suggest that reducing the hypoxia fraction does improve the efficacy of radiation therapy. [7,8,9,10]

Mainly, there are two principal methods to overcome the radiobiological problem of tumour hypoxia [11]:

1. Increasing the delivery of oxygen or oxygen-mimicking agents to the cells: hiperbaric oxygen, carbogen breathing, nicotinamide, increasing oxygen delivery to tissues, blood transfusions, erythropoietin, and hypoxic cell radiosensitizers.

2. Exploiting the special environmental conditions of hypoxic cells using agents that exercise their toxicity under those conditions

Radiation sensitizers mimic the effects of oxygen to increase radiation damage. The most common class of radiation sensitizer that has been evaluated in clinical studies is the nitroimidazoles (eg, misonidazole). However, their major limitation is neurotoxicity, which has prevented the delivery of effective doses with conventional daily fractionated radiation.

An ideal radiation sensitizer would reach the tumour in adequate concentrations and act selectively in the tumour compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today.[12]

Recently, however, with newer molecules that target very specific pathophysiology or molecular pathways and the use of radiation delivered systemically by nanoparticles, antibodies or hormones labeled with radionuclides, the concept of radiation sensitizers has been expanded.

The main purpose of this report is to review the most recent applications of nanoparticles as radiosensitizers in cancer treatment.

Applications of nanoparticles as radiosensitizers in cancer treatment.

Nanoscience is an emerging field that deals with interactions between molecules, cells and engineered substances such as molecular fragments, atoms and molecules. In terms of size constraints, the National Nanotechnology Initiative (NNI) defines nanotechnology in dimensions of roughly 1 to 100 nanometers (nm), [13] but in boarder range it can be extended up to 1000 nm. Particles that fall within this range appear to be optimal for achieving a number of important tasks as nano-carriers, including the alteration of a drug&acirc;€™s reactivity, strength, electrical properties, and ultimately, its behaviour in vivo.

There is great interest in developing new nanodelivery systems for drugs that are already on the market, especially cancer therapeutics. Ideally, nanodelivery systems will allow for more specific targeting of the drug, thereby improving efficacy and minimizing side effects. By using nanotechnology in drug design and delivery, researchers are trying to push nanomedicine to be able to deliver the drug to the targeted tissue, release the drug at a controlled rate, be a biodegradable drug delivery system, and to be able to escape from degradation processes of the body.

Having sprouted from a single concept some years ago, nanotechnology has given rise to nanomedicine, among other applications including those associated with physics, biochemistry, and biotechnology, for creating molecular devices able to facilitate therapeutic and diagnostic procedures on the nanoscale. Thus, applications of nanotechnology have generated immense interest over past decade in various fields for diverse applications.

Some estudies of the application of nanoparticles as radiosensitizers includes germanium nanoparticles. Nanometer-sized germanium particles were fabricated .Comet assay was employed to evaluate the level of DNA Damage indicating that the nanoparticle itself caused a higher level of DNA damage. The possibility that germanium nanoparticles per se caused DNA damage was ruled out when the cellular level of g-H2AX was examined. It has been determined that Nanometer-sized germanium particles were able to enhance the radiosensitivity of cells.[14]

The recent demonstration of nanoscale scintillators has led to interest in the combination of radiation and photodynamic therapy. Scintillating nanoparticles conjugated to photosensitizers and molecular targeting agents would enhance the targeting and improve the efficacy of radiotherapy and extend the application of photodynamic therapy to deeply seated tumors.. Although uncertainties remain, it appears that the light yield of the nanoscintillators, the efficiency of energy transfer to the photosensitizers, and the cellular uptake of the nanoparticles all need to be fairly well optimized to observe a cytotoxic effect. Even so, the efficacy of the combination therapy will likely be restricted to X-ray energies below 300 keV, which limits the application to brachytherapy.[15]

Image-guided radiation treatments (IGRT) routinely utilize radio-opaque implantable devices, such as fiducials or brachytherapy spacers, for improved spatial accuracy. The therapeutic efficiency of IGRT can be further enhanced by biological in situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumour using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs)[16]

The description of a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells was arise by [17]. It was codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48-72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment.

Other studies describe The Nanoparticle Enhanced X-ray Therapy (NEXT), which uses nanomaterials as radiosensitizers to enhance electromagnetic radiation absorption in specific cells or tissues. The nanomaterial radiosensitizers emit Auger electrons and generate radicals in response to electromagnetic radiation, which can cause localized damage to DNA or other cellular structures such as membranes. The nanomaterial radiosensitizers contain moieties for specific targeting to molecules or structures in a cell or tissue, and can be functionalized for increased stability and solubility. The nanomaterial radiosensitizers can also be used as detection agents to help in early diagnosis of disease. Together with known techniques such as Computed Tomography or Computerized Axial Tomography (CT or CAT scan), these nanomaterial radiosensitizers could allow early diagnosis and treatment of diseases such as cancer and HIV. [18]

Paclitaxel and etanidazole are hypoxic radiosensitizers that exhibit cytotoxic action at different mechanisms. The poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles containing paclitaxel, etanidazole and paclitaxel+etanidazole were prepared by emulsification-solvent evaporation method. The drug encapsulation efficiency (EE) and release profile in vitro were measured by high-performance liquid chromatography (HPLC). The cellular uptake of nanoparticles for the human breast carcinoma cells (MCF-7) and the human carcinoma cervicis cells (HeLa) was evaluated by transmission electronic microscopy and fluorescence microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The EE was higher for paclitaxel and lower for etanidazole. The drug release was controlled over time. The cellular uptake of nanoparticles was observed. Co-culture of the two tumor cell lines with drug-loaded nanoparticles demonstrated that released drug effectively sensitized hypoxic tumor cells to radiation. The radiosensitization of paclitaxel+etanidazole nanoparticles was more significant than that of single drug-loaded nanoparticles[19].

The applications of nanoparticles in the radiation therapy have been widely explored. The studies are focused in their ability to carry a known sensitizer to a focused target and also their applications as a sensitizer by itself. As every other new technology, the use nanoparticles involve some risks.

Nanoparticles and toxicity.

Though in recent years there has been a rapid expansion in nanoparticle and nanotechnology research in consumer products, there is limited information on the possible toxic health effects on humans and the environment to date. To assess the toxicity in a systematic manner, there is an urgent need to investigate the intracellular and in vivo fate of the nanoparticulate systems vis-&Atilde; -vis in surface properties and morphology. In an early study by Dunford and colleagues [20] in 1997, it was demonstrated that titanium dioxide/zinc oxide nanoparticles used in sunscreen can catalyze oxidative damage to DNA in vitro and in cultured human fibroblasts. In 2004, at a nanoscale materials and toxicity conference, Nanotox 2004, Vyvvan Howard revealed his initial findings that gold nanoparticles have the ability to move across the placenta from mother to fetus when injected into pregnant rats [21]. There are a few studies that have assessed of toxicity of carbon nanotubes. Shvedova and colleagues [22] hypothesized that the probable dermal toxicity and morphological changes seen were due to accelerated oxidative stress in the skin after having been exposed to the SWCNT. Furthermore, in a separate study, the same group demonstrated that the exposure to unrefined SWCNT may lead to increased pulmonary toxicity due to oxidative stress [23]. Other toxicity studies of carbon nanotubes describe the of cause granulomas in rats and mice after acute exposure [24]. Crystalline silver nanoparticle-related cytoxicity in lesioned skin, growing human fibroblasts, and keratinocytes was demonstrated by Lam and colleagues[25] and Poon and Burd [26]. These studies, among others, have begun to reveal the toxicity of nanoparticles and will pave the way for progression in this field of study.


Each year 10.9 million people worldwide are diagnosed with cancer, and there are 6.7 million deaths from the disease [27]. Approximately half of the people who develop cancer each year receive radiation therapy as a component of their treatment. Delivering a curative dose of radiation to tumour tissues while sparing normal tissues is still a great challenge in radiation therapy.

This review shows the viability of nanoparticles to improve the radiosensitivity in tumours under radiation treatment, increasing the probability of cure in cancer patients. The characteristic of nanoparticles of focusing their action on a specific target decreases the damage on surrounding normal tissues. This characteristic makes the nanoparticles an interesting field of study in radiation therapy.

The biomedical application of nanoparticles has experienced exponential growth in the past few years; however, current knowledge regarding the safety of nanocarriers is insufficient. As these new drug delivery systems are brought to clinical trial one will begin to be able to identify any negative side effects associated with these compounds [28]. Preliminary and complementary animal studies should be carried out to identify the risks associated with nanoparticle use, with particular attention paid to the elimination processes. Furthermore, very little attention has been paid to the environmental effects and the potential effects on the health of those manufacturing these particles. Considering the countless potential applications of nanoparticles in the health sector, particularly in cancer research, there is an urgent need for the development of safety guidelines.

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