# Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery > **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $440,959 ## 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 β-cell function and/or stimulate β-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 β-cell regeneration, β-cell preservation, and immune-protection. In principle, stimulating the regeneration of insulin- producing β-cells could be used to restore or enhance endogenous insulin production capacity. Recently, we developed several new highly potent chemical inducers of human β-cell proliferation. However, the non-selective growth-promoting activity of these molecules prevents further clinical development. Consequently, a “modular” (readily transferable) system for β-cell-targeted drug delivery is needed to realize the next generation of diabetes therapeutics. To address this challenge, we are developing a β-cell-targeted drug delivery module based upon the uniquely high zinc content of β-cells. In this system, a zinc-chelating moiety is covalently integrated into a replication-promoting (cargo) compound to generate a bi-functional compound (βRepZnC) that selectively enhances β-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 β-cell-targeted drug delivery. In Aim 1, we will define the chemical “rules” that govern zinc-dependent β-cell targeting. We will synthesize and assay diverse βRepZnCs where cargo/chelator composition, zinc-binding affinity and physicochemical properties are systematically varied. In Aim 2, we will examine the in vivo β-cell selectivity (accumulation and replication-promoting activity) of systemically-delivered βRepZnCs. 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 βRepZnC 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 β-cell zinc and zinc- binding drug accumulation. As part of this effort, we will genetically enhance β-cell βRepZnCs accumulation and β-cell selective replication induction. Overall, our studies will advance a modular technology for β-cell-targeted drug delivery, optimize βRepZnCs, validate a greatly needed tool for assessing cell-targeted drug delivery in viv... ## Key facts - **NIH application ID:** 10366072 - **Project number:** 5R01DK101530-07 - **Recipient organization:** STANFORD UNIVERSITY - **Principal Investigator:** Justin Pierce Annes - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $440,959 - **Award type:** 5 - **Project period:** 2015-09-01 → 2025-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10366072 ## Citation > US National Institutes of Health, RePORTER application 10366072, Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery (5R01DK101530-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366072. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*