Joseph DeSimone Image Map
Apr 302014
Fig. 1. Ex vivo fluorescent imaging of harvested organs allows for assessment of particle biodistribution, to illustrate where particles accumulate when administered intravenously. Here we observe that 55 x 77 nm PEGylated hydrogel PRINT particles accumulate mainly in clearance organs – liver and spleen, as well as in primary flank xenograft tumors, with  minimal accumulation in the lung and kidneys.

Despite decades of research and development to improve our ability to diagnose and treat cancer in all its varied and insidious forms, cancer is poised to overtake heart disease as the number one cause of death in the United States in the coming years. Increases in life expectancy broadly will only add to the number of people afflicted with cancer, exacerbating an already intransigent health care burden. Furthermore, our standard means of treating many cancers with systemic chemotherapies takes a significant toll on the quality of life for patients. Because systemic chemotherapy exposes the entire body to toxic chemicals, with only a small portion actually reaching cancer cells, patients often experience significant side effects and poor treatment efficacy. Thus, it is thought that drug delivery devices that can target diseased tissue while sparing systemic exposure will limit the toxicity of standard chemotherapy regimens while increasing treatment efficacy.

To this end, the Desimone lab’s cancer research program aims to design novel nanoscale delivery devices to improve cancer outcomes. By using precise control of nanoparticle (NP) fabrication, our goal is to identify the optimal characteristics to design NPs that enhance chemotherapy. The Particle Replication In Non-wetting Templates (PRINT) platform has been utilized to fabricate novel cross-linked hydrogel and poly(lactide-co-glycolide) (PLGA) particles with controllable size, shape, drug loading, modulus, surface chemistry, targeting ligand density and therapeutic release kinetics using multiple triggered linkers for chemotherapeutics and siRNA. Manufacturing control over these variables enables iterative understanding of how particle designs interface with biological systems, generating actionable information that can be used to improve therapeutic outcomes for cancer.

For example, plasma circulation time of particles can be controlled by size, surface chemistry and modulus, enabling tailoring of therapies to specific cancers and sites of disease in the body. In addition, chemical conjugation strategies can be used to augment the kinetics of drug release, which limits systemic exposure and enhances the maximum tolerated dose (MTD) of chemotherapeutics. Combining these approaches using PRINT NPs has resulted in prolonged survival in multiple preclinical animal models through improved tumor accumulation and increased MTD. Further studies are being conducted to optimize surface chemistry of particles with targeting ligands to enhance tumor uptake and retention. Given the tremendous complexity of cancer, be it the molecular pathways implicated or the variability in tumor location, the modular control of drug delivery devices may enable substantial advances in cancer treatment.

 April 30, 2014
Mar 192014
wong_dominica_pnasDominica Wong’s work has been highlighted in a PNAS Commentary by Liangbing Hu and Kang Xu from the University of Maryland and the U.S. Army Research Laboratory respectively. The piece focuses on Wong’s research on the use of perfluoropolyethers (PFPEs) as electrolytes for lithium ion batteries. Noting that the research is an encouraging advance toward a safer lithium ion battery, the authors also suggest that the work could have benefits “beyond lithium ion” battery chemistry as well.
 March 19, 2014
Jan 282014

MolecMosqIMAGE_Jan2014It is estimated that well over half a billion people worldwide are infected every year by pathogens transmitted by mosquito bites. Malaria and Dengue fever are two of the most debilitating mosquito-borne diseases, and many others wreak havoc throughout the world. Traditional approaches to mosquito control include the use of chemical sprays such as insecticides that contaminate crops, pollute waters and permeate the food chain with unexpected and unplanned off-target effects. In addition, mosquitoes can develop resistance to chemical sprays, thus greatly limiting their efficacy over time and further damaging the environment through increased use of these toxins.

The molecular mosquitocide (MM) program is a research effort in collaboration with faculty from Colorado State University (Barry Beaty) and Iowa State (Lyric Bartholomay) aimed at fundamentally changing how we control mosquito populations. By using the endogenous RNA interference (RNAi) pathway found throughout the animal kingdom, the goal of the MM program is to deliver RNA sequences via nanoparticles that target mosquito genes required for disease-transmission. Such RNA sequences may prevent mosquito reproduction or may impede mosquitoes from providing an environment suitable to host pathogens which cause human disease. These RNA sequences are both species and gene-specific, thus preventing resistance development and the panoply of off-target effects that current chemical spraying methods engender. Critically, nanoparticles shield RNA from rapid degradation and promote systemic biodistribution, two parameters integral to the eventual efficacy of the MM approach.

Initial studies are clarifying the role of size, shape and charge on the biodistribution of PRINT nanoparticles in Anopheles gambiae, the mosquito species which carries and transmits the causative agent of malaria (Figure 1). Using the inherent fabrication control of PRINT, these studies will help broaden our understanding of how particle parameters augment distribution throughout individual mosquito species at different stages of life (e.g., larvae and adults) with the aim of developing more tailored and efficacious molecular mosquitocides. For example, RNA sequences targeting mosquito genes involved in egg development will likely need to target the abdomen of adult mosquitoes, whereas targeting of the feeding cycle will require nanoparticles which can deliver RNA to the head of the mosquito. The molecular mosquitocide program combines the explosion of information accrued in mosquito genetics and genomics with the delivery capabilities of PRINT nanoparticles to provide an almost unlimited number of potential target genes and sequences for RNAi-based MMs.

 January 28, 2014