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：
10207073
负责人：
Justin Pierce Annes
金额：
$ 43.62万
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/10207073
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 Image 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 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.

项目摘要糖尿病是一种葡萄糖稳态疾病，会导致过度住院，发病率和早期死亡率在受疾病影响的美国人中超过3420万。因此，开发药理学保持β细胞功能和/或刺激β细胞质量扩张的方法引起了人们的强烈关注。目前，安全治疗靶标的死亡使改善的糖尿病药物的创造受到阻碍。实际上，目标但是组织外药物的影响正在减慢多种糖尿病治疗域的进展，包括β细胞再生，β细胞保存和免疫保护。原则上，刺激胰岛素的再生产生的β细胞可用于恢复或增强内源性胰岛素生产能力。最近，我们开发了人类β细胞增殖的几种新型高潜在的化学诱导剂。但是，非选择性这些分子的增长活性阻止了进一步的临床发育。因此，“模块化” （随时转移）用于实现下一代糖尿病的β细胞靶向药物的系统治疗。为了应对这一挑战，我们正在基于 β细胞的独特锌含量。在该系统中，将锌螯合部分共价集成到一个复制促进（货物）化合物以产生有选择性的双功能化合物（βrepznc）增强β细胞药物的积累和复制促进活性。在这里，我们结合了医学化学努力进行系统的体外和体内询问，以推进我们针对β细胞靶向药物的平台技术送货。在AIM 1中，我们将定义依赖锌细胞靶向锌的化学“规则”。我们将合成和分析潜水员βRepznc，其中货物/螯合剂组成，锌结合亲和力和物理特性是系统的。在AIM 2中，我们将检查体内β细胞选择性（累积和复制促进活性）全身传递的βrepzncs。我们将使用解吸电喷雾电离质谱法（DESI-MSI）测量组织特异性药物的积累并预测组织特异性生物活性。这项工作将证明新型βrepznc治疗在体内效率多种糖尿病小鼠模型并提供经过验证的方法；克服发展的主要障碍细胞靶向疗法：缺乏用于组织特异性药物递送体内测量的便捷方法。在AIM 3中，我们将使用CRISPR技术在基因上剖析控制β细胞锌和锌的途径结合药物积累。作为这项工作的一部分，我们将一般会增强β-CellβRepzncs的积累和 β细胞选择性复制诱导。总体而言，我们的研究将推进针对β细胞靶向的模块化技术药物输送，优化βRepzncs，验证了一种在体内评估细胞靶向药物递送的急需的工具并为β细胞生物学提供基本的（目标）见解。