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

项目摘要 1型糖尿病的特征在于β细胞质量的损失和胰岛素产生能力的降低。因此，在本发明中， 开发一种刺激β细胞团扩增的药理学方法具有巨大的潜力， 治疗价值最近，我们的团队和其他人成功地开发了高效的小分子 人类β细胞增殖的诱导剂;然而，这些分子的促生长活性是非 选择性的因此，诱导脱靶细胞增殖的可能性是安全性的主要障碍。 这些再生化合物在人类中的应用。在此，一种新的，可推广的前药策略， 将开发选择性地将再生治疗剂递送到β细胞。该战略利用了一个独特的 β-细胞将潜在前药转化为生物活性子化合物的生物活性。基于先前的 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， 递送到这种新的前药策略中;包括在抗体中使用的分子接头的掺入-和 确保化合物在生物活化之前完全潜伏且无疤痕的小分子药物缀合物 生物活化后。此外，前药激活的细胞机制将得到阐明。这项工作 将提供一个强大的，基于里程碑的数据包，用于β细胞靶向药物递送，包括深度 了解前药生物活性，构效关系数据，药代动力学表征， 细胞类型特异性活性和体内功效与人胰岛为基础的临床前模型。复制活动 将在短期和长期化合物暴露后评估靶组织（β细胞）和脱靶组织; 证明这种β细胞靶向治疗递送的持续特异性和有效性的关键研究 战略这些研究有可能提供安全的、潜在的变革性的、一流的铅 用于再生治疗糖尿病的化合物。关键是，开发的技术可用于β细胞- 几乎所有治疗药物的靶向递送。

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.