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

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

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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.

项目摘要 1型糖尿病的特征是β细胞质量的丧失和胰岛素生产能力降低。那，开发一种用于刺激β细胞质量膨胀的药理学方法具有巨大的潜力治疗价值。最近，我们的小组和其他人成功地开发了高效的小分子人β细胞增殖的诱导者；但是，这些分子的生长促进活性是非 - 选择性。因此，引起靶向脱靶细胞增殖的潜力是安全的主要障碍在人类中使用这些再生化合物。以下是一种新颖的，可概括的前药策略将开发将调节疗法的选择性递送到β细胞。该策略利用了独特的 β细胞将潜在前药转化为生物活性子化合物的生物学活性。基于先验成功，将通过纳入针对性药物的更广泛领域的相关进展来进一步进步交付这种新的前药策略；包括掺入抗体和小分子 - 药物缀合物，可确保化合物在生物活化之前完全潜在，并且被释放生物活化后。另外，将阐明前药激活的细胞机制。这项工作将为β细胞的靶向药物提供一个强大的基于里程碑的数据包，其中包括深层了解前药生物活化，结构活性关系数据，药代动力学表征，基于人类胰岛的临床前模型，细胞类型特异性活性和体内效率。复制活动在短期和长期复合暴露后，将评估目标（β细胞）和脱靶时机；研究至关重要，以证明该β细胞靶向治疗的持续特异性和效率战略。这些研究有可能提供安全的，潜在的变革性，一流的铅用于再生治疗糖尿病的化合物。至关重要的是，开发的技术可用于β细胞有针对性的几乎所有治疗性。