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Developing A Platform Technology For β-Cell-Targeted Drug Delivery

开发β细胞靶向药物输送的平台技术

基本信息

批准号：
10729390
负责人：
Justin Pierce Annes
金额：
$ 55.62万
依托单位：
STANFORD UNIVERSITY
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729390
关键词：
Antibodies Autonomous Replication Beta Cell Biochemical Biological Biological Assay Biology Cell Lineage Cell Membrane Permeability Cell Proliferation Cell membrane Cell surface Cells Cellular Assay Chemicals Coculture Techniques Data Daughter Dependence Diabetes Mellitus Diabetic mouse Dose Drug Delivery Systems Drug Kinetics Drug Targeting Endosomes Ensure Functional disorder Generations Goals Histology Human Human Cell Line Impairment In Vitro Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Lead Measures Mediating Membrane Methods Modeling Molecular Mus Natural regeneration Neuroendocrine Cell Pathologic Pharmaceutical Chemistry Pharmaceutical Preparations Pre-Clinical Model Prodrugs Production Protein Isoforms Recombinants Secretory Vesicles Specificity Structure-Activity Relationship Technology Therapeutic Tissues Transplantation Treatment Efficacy Work biophysical properties blood glucose regulation cell type cellular targeting design extracellular glucose tolerance growth promoting activity humanized mouse in vivo innovation islet next generation novel peptidylglycine alpha-amidating monooxygenase pharmacologic pre-clinical prevent regenerative regenerative therapy regenerative treatment restoration screening small molecule success targeted delivery targeted treatment technology platform trafficking

项目摘要

PROJECT SUMMARY Type 1 diabetes is characterized by the loss of β-cell mass and decreased insulin production capacity. Thus, developing a pharmacologic method for stimulating the expansion of β-cell mass has substantial potential therapeutic value. Recently, our group and others have successfully developed highly potent small-molecule inducers of human β-cell proliferation; however, the growth-promoting activity of these molecules is non- selective. Consequently, the potential for inducing off-target cellular proliferation is a primary barrier to the safe use of these regenerative compounds in humans. Herein, a novel, generalizable prodrug strategy for the selective delivery of regerative therapeutics to the β-cell will be developed. The strategy leverages a unique biologic activity of the β-cell to convert latent prodrugs into bioactive daughter compounds. Building on prior success, progress will be furthered by incorporating relevant advances made in the broader field of targeted drug delivery into this new prodrug strategy; including the incorporation of molecular linkers used in antibody- and small molecule-drug conjugates that ensure compounds are fully latent prior to bioactivation and are unscarred following bioactivation. Additionally, the cellular mechanisms of prodrug activation will be elucidated. This work will deliver a robust, milestone-based data package for β-cell targeted drug delivery that includes a deep understanding of prodrug bioactivation, structure-activity relationship data, pharmacokinetic characterization, cell-type-specific activity and in vivo efficacy with a human islet-based preclinical model. The replicative activity of target (β-cells) and off-target tissues will be assessed following short-term and long-term compound exposure; studies critical to demonstrating the sustained specificity and efficacy of this β-cell targeted therapeutic delivery strategy. These studies have the potential to deliver safe, potentially transformative, first-in-class lead compounds for regenerative treatment of diabetes. Critically, the developed technology may be used for β-cell- targeted delivery of nearly any therapeutic.

项目总结