Developing A Platform Technology For β-Cell-Targeted Drug Delivery

项目总结 1型糖尿病的特征是β细胞团的丧失和胰岛素产生能力的降低。因此， 开发一种刺激β细胞团扩张的药理学方法具有巨大的潜力 治疗价值。最近，我们团队和其他人成功地开发出了高度有效的小分子 人β细胞增殖的诱导剂；然而，这些分子的促生长活性是非 有选择性的。因此，诱导靶外细胞增殖的可能性是安全的主要障碍。 这些再生化合物在人类身上的使用。在此，一种新颖的、可推广的前药策略可用于 将开发选择性地将再生疗法输送到β-细胞。该战略利用了独特的 β细胞将潜伏的前体药物转化为生物活性子体化合物的生物活性。在以前的基础上构建 为了取得成功，将通过纳入在更广泛的靶向药物领域取得的相关进展来推动进展 进入这一新的前药策略；包括纳入用于抗体的分子连接物-和 小分子-药物结合物，确保化合物在生物激活前完全潜伏且无疤痕 在生物激活之后。此外，还将阐明前药激活的细胞机制。这部作品 将为β细胞靶向药物传递提供一个强大的、基于里程碑的数据包，其中包括深度 了解前药的生物活性，构效关系数据，药代动力学特性， 以人类胰岛为基础的临床前模型的细胞类型特异性活性和体内疗效。复制活动 在短期和长期复合暴露后，将评估靶(β细胞)和靶外组织的数量； 对证明这种β细胞靶向治疗药物的持续特异性和有效性至关重要的研究 策略。这些研究有可能提供安全的、潜在的变革性、一流的领先优势 用于糖尿病再生治疗的化合物。关键是，开发的技术可能用于β-CELL- 几乎所有的治疗方法都是有针对性的。

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.