Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery

Stanford University, Stanford CA

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Abstract

PROJECT SUMMARY Diabetes is a disorder of glucose homeostasis that causes excess hospitalization, morbidity and early mortality among the more than 34.2 million disease-affected Americans. Consequently, developing pharmacologic methods to preserve ?-cell function and/or stimulate ?-cell mass expansion is of intense interest. Presently, the creation of improved diabetes medications is stymied by a dearth of safe therapeutic targets. In fact, on-target but off-tissue drug effects are slowing progress across multiple diabetes therapeutic domains including ?-cell regeneration, ?-cell preservation, and immune-protection. In principle, stimulating the regeneration of insulin- producing ?-cells could be used to restore or enhance endogenous insulin production capacity. Recently, we developed several new highly potent chemical inducers of human ?-cell proliferation. However, the non-selective growth-promoting activity of these molecules prevents further clinical development. Consequently, a ?modular? (readily transferable) system for ?-cell-targeted drug delivery is needed to realize the next generation of diabetes therapeutics. To address this challenge, we are developing a ?-cell-targeted drug delivery module based upon the uniquely high zinc content of ?-cells. In this system, a zinc-chelating moiety is covalently integrated into a replication-promoting (cargo) compound to generate a bi-functional compound (?RepZnC) that selectively enhances ?-cell drug accumulation and replication-promoting activity. Here, we combine a medicinal chemistry effort with systematic in vitro and in vivo interrogation to advance our platform technology for ?-cell-targeted drug delivery. In Aim 1, we will define the chemical ?rules? that govern zinc-dependent ?-cell targeting. We will synthesize and assay diverse ?RepZnCs where cargo/chelator composition, zinc-binding affinity and physicochemical properties are systematically varied. In Aim 2, we will examine the in vivo ?-cell selectivity (accumulation and replication-promoting activity) of systemically-delivered ?RepZnCs. We will use desorption electrospray ionization mass spectrometry (DESI-MSI) to measure tissue-specific drug accumulation and predict tissue-specific bioactivity. This work will demonstrate the in vivo efficacy of novel ?RepZnC therapeutics in multiple diabetes mouse models and deliver a validated methodology; overcoming a major barrier to developing cell-targeted therapeutics: the lack of a facile method for in vivo measurement of tissue-specific drug delivery. In Aim 3, we will use CRISPR technology to genetically dissect the pathways that control ?-cell zinc and zinc- binding drug accumulation. As part of this effort, we will genetically enhance ?-cell ?RepZnCs accumulation and ?-cell selective replication induction. Overall, our studies will advance a modular technology for ?-cell-targeted drug delivery, optimize ?RepZnCs, validate a greatly needed tool for assessing cell-targeted drug delivery in vivo and provide fundamental (targetable) insights into ?-cell biology.