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

项目摘要 聚合物纳米颗粒为口服药物提供了一个令人兴奋的机会。虽然前景看好， 这种方法目前受到两个主要问题的限制：1)缺乏用于定制的通用聚合物结构 提供不同的药物，以及2)缺乏能够预先预测临床的量化工具 口服载药聚合物纳米粒的药代动力学和药效学。在追捕中 关于聚合物纳米粒子的临床翻译，本建议旨在合成具有受控性质的聚酯 用于探测肠-血屏障的跨细胞作用的拓扑结构和开发形式的定量工具 数学系统基于生理的药代动力学(PBPK)模型。为了实现这一目标，一系列的 在翻译相关的临床前物种的体外、体内和电子研究中，建议获得 对负责吸收、分配、新陈代谢和 载药聚合物纳米粒的消除(ADME)。此外，所有临床前数据都将 使用一种新的自下而上系统PBPK模型同时进行数学集成，该模型可以用作 口服载药聚合物纳米粒临床前到临床转化的定量工具。

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.