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