Prodrug engineering for enhanced biodistribution and pharmacokinetics

Project Summary Small molecular drugs play a pivotal role in treating a wide range of diseases, such as cancer, infection, cardiovascular diseases, and various other ailments. However, many of these small molecular drugs, suffer from limited solubility, severe side effects, and unsatisfactory efficacy due to unfavorable pharmacokinetics and inefficient drug delivery to diseased sites. Drug delivery systems, including antibody-drug conjugates, polymeric micelles, liposomes, polymer-drug conjugates, and nanoparticles, have been widely used to improve pharmacokinetics and biodistribution, ultimately leading to enhanced therapeutic efficacy and reduced adverse effects. Yet, delivery of therapeutic agents is unsatisfactory in many cases. There is a pressing need for the development of innovative delivery approaches for a vast variety of therapeutic agents. Toward this end, two novel strategies designed to improve the biodistribution and pharmacokinetics of small molecular drugs, especially those with unfavorable physiochemical properties toward conventional drug delivery systems are proposed: 1) Development of albumin-binding targeted prodrug; 2) Targeted responsive polymer prodrugs with tunable drug release. On one hand, we aim to design and synthesize an albumin-binding targeted small molecule drug conjugates consisting of a targeting ligand, an albumin- binder that can hitchhike endogenous albumin as a carrier, and a highly potent drug linked via responsive linker. We will systematically investigate the effect of the payload linker chemistry, albumin binding, and targeting ligands on the in vitro self-assembly, drug release, cellular uptake, and cytotoxicity, and in vivo pharmacokinetics, biodistribution, and therapeutic efficacy. On the other hand, we propose to use prodrug- initiated ring opening polymerization (ROP) to obtain a polymer prodrug in one step. We will investigate the effect of prodrug polymer chain length on the prodrug hydrophobicity and loading efficiency and capacity, the formation of stereocomplexes with the nanocarrier, and release kinetics, cellular uptake, in vitro cytotoxicity, and therapeutic efficacy in vivo. The outcome of this research proposed is to establish modular platforms toward the safe and effective delivery of therapeutic agents leveraging advances in organic and polymer chemistry, materials science, and nanomedicine. The proposed research focuses on engineering prodrugs for improved drug delivery which features improved pharmacokinetics, biodistribution, and therapeutic efficacy with reduced systemic toxicities. We will establish rules and principles to guide the design and development of albumin-binding targeted prodrugs and responsive polymer prodrugs. Our innovative strategies can be applied to a diverse array of therapeutic agents and will have a transformative impact in the field of drug delivery and offer tremendous opportunities in disease treatment.