Polyesters with controlled topologies for probing transcytosis at the gut-blood barrier

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Project Summary Polymer nanoparticles present an exciting opportunity to deliver pharmaceutical drugs orally. While promising, this approach is currently limited by two major problems, 1) lack of versatile polymer structures for customized delivery of diverse pharmaceutical drugs and 2) lack of quantitative tools that can a priori predict clinical pharmacokinetics and pharmacodynamics of orally administered drug-laden polymer nanoparticles. In pursuit of clinical translation of polymer nanoparticles, this proposal aims to synthesize polyesters with controlled topologies for probing transcytosis at the gut-blood barrier and develop quantitative tools in the form of mathematical systems physiologically based pharmacokinetic (PBPK) models. Towards this goal, a series of in vitro, in vivo, and in silico investigations in translationally relevant preclinical species are proposed to obtain unprecedented quantitative insight into the processes responsible for absorption, distribution, metabolism, and elimination (ADME) of drug-laden polymer nanoparticles. In addition, all the preclinical data will be mathematically integrated simultaneously using a novel bottom-up systems PBPK model, which can serve as a quantitative tool for preclinical-to-clinical translation of orally administered drug-laden polymer nanoparticles.