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

具有受控拓扑的聚酯用于探测肠血屏障的转胞吞作用

基本信息

批准号：
10658083
负责人：
Ravikumar N Majeti
金额：
$ 32.84万
依托单位：
UNIVERSITY OF ALABAMA IN TUSCALOOSA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658083
关键词：
ABCB1 gene Affinity Behavior Binding Sites Biological Availability Blood Blood - brain barrier anatomy Blood-Retinal Barrier Canis familiaris Cannulations Cells Characteristics Chemistry Cyclosporine Data Designer Drugs Development Dose Drug Carriers Drug Delivery Systems Drug Transport Encapsulated Engineering Excipients Exhibits Family suidae Goals Growth Health Technology Human In Vitro Intestines Investigation Knockout Mice Knowledge Lead Length Ligand Binding Ligands Mathematics Mechanics Mediating Metabolism Modeling Modification Mus Nanostructures Oral Oral Administration Peptide Hydrolases Performance Periodicals Pharmaceutical Preparations Pharmacologic Substance Physiology Polyesters Polymers Portal vein structure Process Property Race Rattus Receptor Cell Regimen Research Research Personnel Rodent Role Route Scheme Series Structure Structure-Activity Relationship Surface System TFRC gene Tea Toluene Transferrin Translations Vertebral column Work absorption amphiphilicity clinical practice clinical predictors clinical translation data modeling density design drug repurposing drug-like compound extracellular flexibility functional group gambogic acid hydrophilicity improved in silico in vivo insight lymphatic duct mathematical model mouse model nanocarrier nanomedicine nanoparticle nanopolymer nanosystems new chemical entity next generation novel novel strategies pharmacokinetic model pharmacokinetics and pharmacodynamics physiologically based pharmacokinetics pre-clinical rational design receptor receptor mediated endocytosis small molecule stoichiometry technology platform tool trafficking transcytosis uptake

项目摘要

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.

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。