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Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery

利用独特的高β细胞锌含量进行靶向药物输送

基本信息

批准号：
10366072
负责人：
Justin Pierce Annes
金额：
$ 44.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366072
关键词：
Address Affect Affinity American B Cell Proliferation Beta Cell Binding Biochemical Biological Biological Assay Biophysics CRISPR/Cas technology Cell physiology Cells Cellular biology Chelating Agents Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Development Diabetes Mellitus Diabetic mouse Disease Disease model Dose Drug Delivery Systems Drug Exposure Drug Kinetics Drug Targeting Functional disorder Genes Genetic Hospitalization Human Immune In Vitro Insulin Islets of Langerhans Transplantation Measurement Measures Methodology Methods Modeling Molecular Molecular Target Morbidity - disease rate Mus Natural regeneration Organ Pathologic Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Production Property Rodent Series Solubility Spectrometry, Mass, Electrospray Ionization Streptozocin Structure-Activity Relationship System Technology Therapeutic Tissues Transplantation Work Zinc base biophysical properties blood glucose regulation cell regeneration chelation chemical genetics clinical development diabetic drug metabolism efficacy validation experience experimental study growth promoting activity improved in vivo insight interest islet mass spectrometric imaging mortality next generation novel pre-clinical preservation prevent regenerative regenerative therapy targeted delivery targeted treatment therapeutic target tool

项目摘要

PROJECT SUMMARY Diabetes is a disorder of glucose homeostasis that causes excess hospitalization, morbidity and early mortality among the more than 34.2 million disease-affected Americans. Consequently, developing pharmacologic methods to preserve β-cell function and/or stimulate β-cell mass expansion is of intense interest. Presently, the creation of improved diabetes medications is stymied by a dearth of safe therapeutic targets. In fact, on-target but off-tissue drug effects are slowing progress across multiple diabetes therapeutic domains including β-cell regeneration, β-cell preservation, and immune-protection. In principle, stimulating the regeneration of insulin- producing β-cells could be used to restore or enhance endogenous insulin production capacity. Recently, we developed several new highly potent chemical inducers of human β-cell proliferation. However, the non-selective growth-promoting activity of these molecules prevents further clinical development. Consequently, a “modular” (readily transferable) system for β-cell-targeted drug delivery is needed to realize the next generation of diabetes therapeutics. To address this challenge, we are developing a β-cell-targeted drug delivery module based upon the uniquely high zinc content of β-cells. In this system, a zinc-chelating moiety is covalently integrated into a replication-promoting (cargo) compound to generate a bi-functional compound (βRepZnC) that selectively enhances β-cell drug accumulation and replication-promoting activity. Here, we combine a medicinal chemistry effort with systematic in vitro and in vivo interrogation to advance our platform technology for β-cell-targeted drug delivery. In Aim 1, we will define the chemical “rules” that govern zinc-dependent β-cell targeting. We will synthesize and assay diverse βRepZnCs where cargo/chelator composition, zinc-binding affinity and physicochemical properties are systematically varied. In Aim 2, we will examine the in vivo β-cell selectivity (accumulation and replication-promoting activity) of systemically-delivered βRepZnCs. We will use desorption electrospray ionization mass spectrometry (DESI-MSI) to measure tissue-specific drug accumulation and predict tissue-specific bioactivity. This work will demonstrate the in vivo efficacy of novel βRepZnC therapeutics in multiple diabetes mouse models and deliver a validated methodology; overcoming a major barrier to developing cell-targeted therapeutics: the lack of a facile method for in vivo measurement of tissue-specific drug delivery. In Aim 3, we will use CRISPR technology to genetically dissect the pathways that control β-cell zinc and zinc- binding drug accumulation. As part of this effort, we will genetically enhance β-cell βRepZnCs accumulation and β-cell selective replication induction. Overall, our studies will advance a modular technology for β-cell-targeted drug delivery, optimize βRepZnCs, validate a greatly needed tool for assessing cell-targeted drug delivery in vivo and provide fundamental (targetable) insights into β-cell biology.

项目总结