Modular, degradable, polymeric nanoparticles for the treatment of phagocyte-mediated diseases

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Nanoparticle (NP) drug delivery systems enable the protection of therapeutic cargoes with tunable target specificity. Polymeric NPs exhibit phagocytic tropism, accumulating in the reticuloendothelial system of the liver and spleen. This property is a barrier to non-phagocyte drug delivery but a boon for the development of phagocyte-mediated disease therapies. We have developed a highly tunable, biodegradable NP platform composed of poly(amine-co-ester) (PACE) polymers that has been successfully utilized to deliver nucleic acids to various tissues. We have demonstrated that NP design and administration variables dictate the organ and cellular biodistribution of PACE NPs. How these variables dictate biodistribution to specific phagocyte subpopulations and how these principles are modulated in the presence of phagocyte-mediated disease are unknown. This proposal outlines a four-year training program for Dr. Thomas C. Binns, MD – enabling his development into an independent investigator with expertise in understanding NP-phagocyte interactions with the goal of developing novel drug delivery approaches for the treatment of phagocyte-mediated diseases. Dr. Binns will study how PACE NP design/administration principles influence uptake in hepatic and splenic phagocyte subpopulations during health and disease. The most important NP design variables – size, charge, stiffness, surface hydrophobicity, and dose – will be evaluated, as we have previously demonstrated that these variables influence biodistribution on the organ and cellular scales. Dr. Binns will carry out these investigations in established murine models of health (Aim 1) and antibody-mediated erythrophagocytosis (AME; Aim 2). This work addresses an area of unmet medical need: AME defines several diseases including warm autoimmune hemolytic anemia, a disease with an estimated 40,000 patient US prevalence, 50% relapse rate, and 10% mortality. A novel treatment option with a long duration of activity and/or a lower drug-mediated morbidity profile could significantly change the therapeutic paradigm for patients with relapsed/refractory disease. Findings will be leveraged to develop a preclinical nucleic acid therapeutic for AME facilitated by PACE NP delivery (Aim 3). Dr. Binns has assembled a team of experts in polymer synthesis, NP formulation, nucleic acid therapeutic design, antibody-erythrocyte interactions, and phagocyte biology/phenotyping who will provide experimental insights, technique advisement, and career mentorship. He will gain training in polymer synthesis, sophisticated data acquisition and analysis (e.g., highly-multiplexed flow cytometry), drug development/translation, and laboratory management in an environment conducive to training physician- scientists. These skills will enable Dr. Binns to successfully transition to an independent position with the goal of developing drug delivery approaches for the immunomodulation of phagocytes.