UCSF

Small molecules and protein therapeutics are constantly being developed due to their high potency and biological function, but there are many barriers that reduce the therapeutic efficacy of these compounds such as short half-life leading to high clearance, and biological degradation. As a result, to overcome these challenges typically higher doses have to be administered with increased frequency to reach a therapeutically relevant concentration. To address these issues nano- and micro- technology has been utilized to increase drug absorption. This dissertation presents various approaches to drug delivery based on the disease target, application, and therapeutic compound. We showed with hydrogel microdevices a reversible increase in intestinal efflux transporters P-glycoprotein and Breast Cancer Resistance Protein, resulting in an increase in drug absorption. We demonstrate in a Caco-2 model that this decrease in efflux transporter function was due to a decreased amount of transporter present on the cell surface in the presence of microdevices. Also, presented are two polymer nanoparticle-based system designed for different disease targets. First, for cancer immunotherapy we designed a nanoparticle loaded with an adjuvant cocktail with a tumor specific peptide to promote antigen presenting cell activation and downstream lead to tumor specific T cell activation. Therapeutically, these drug-loaded nanoparticles were able to decrease tumor volume in a subcutaneous melanoma model and melanoma foci in a metastasis model. Second, in atherosclerosis where arteries were damaged, we showed that tissue factor peptide targeted nanoparticles loaded with an anti-inflammatory agent were able to target desired damaged arteries where tissue factor is typically exposed. The strategies presented here expand the application of nano- and micro- technology to be designed and implemented in a variety of different disease and targets to increase drug absorption and efficacy not only by increase drug half-life but by targeting the therapeutics to desired regions to increase local concentrations.