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.

项目概要 1 型糖尿病的特点是 β 细胞质量损失和胰岛素产生能力下降。开发一种刺激β细胞质量扩张的药理学方法具有巨大的潜力最近，我们组和其他人成功开发了高效小分子。人类 β 细胞增殖的诱导剂；然而，这些分子的生长促进活性是非经过选择性检查，诱导脱靶细胞增殖的潜力是安全的主要障碍。本文提出了一种新颖的、可推广的前药策略。该策略利用了一种独特的方法，选择性地向 β 细胞递送再生疗法。 β细胞将潜在前药转化为生物活性子化合物的生物活性。如果取得成功，将通过纳入更广泛的靶向药物领域取得的相关进展来进一步推动进展递送到这种新的前药策略中；包括掺入用于抗体和药物的分子接头；小分子药物缀合物，确保化合物在生物激活之前完全潜伏且无疤痕此外，这项工作还将阐明前药激活的细胞机制。将为 β 细胞靶向药物递送提供强大的、基于里程碑的数据包，其中包括深入的了解前药生物活性、结构-活性关系数据、药代动力学特征、基于人类胰岛的临床前模型的细胞类型特异性活性和体内功效。将在短期和长期化合物暴露后评估目标（β细胞）和非目标组织的情况；对于证明这种 β 细胞靶向治疗递送的持续特异性和功效至关重要的研究这些研究有可能提供安全的、具有潜在变革性的一流先导药物。至关重要的是，所开发的技术可用于 β 细胞。几乎任何治疗的靶向递送。