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

• 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
• 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

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。因此， 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 治疗价值。近期，我们课题组等成功开发出高效小分子 人类β细胞增殖诱导剂；然而，这些分子的生长促进活性是非- 有选择性的。因此，诱导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。在此，一种新颖的、可推广的前药策略 将开发向β细胞选择性递送再生疗法。该战略利用了独特的 β细胞将潜在前药转化为生物活性子化合物的生物活性。建立在先前的基础上 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 交付到这一新的前药战略；包括掺入抗体和中使用的分子接头 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 生物活化后。此外，还将阐明前药激活的细胞机制。这部作品 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。复制活动 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 战略。这些研究有可能提供安全、具有潜在变革性、一流的领先药物 用于糖尿病再生治疗的化合物。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。