Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells.

Miseon Lee,Rohit N Kulkarni,Stephen J Lippard,Debasish Manna,Amedeo Vetere,Praveen Kokkonda,Amit Choudhary,Basudeb Maji,Jacob M Goldberg,Sevim Kahraman,Bridget K Wagner,Ruth M Elgamal,Jonnell Small

doi:10.1021/jacs.0c00099

Abstract

The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging. However, the lack of β-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in β-cells over other islet cells ex vivo or other cell-types in an organismal context will be immensely valuable in advancing diabetes research and therapeutic development. Here, we leverage the unusually high Zn(II) concentration in β-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to β-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in β-cells as compared to other pancreatic cells; importantly, Zn(II)-mediated hydrolysis triggers cargo activation. This prodrug system, with modular components that allow for fine-tuning selectivity, should enable the safer and more effective targeting of β-cells.

Highlights

The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging
We demonstrate the selective release of multiple fluorophores and a β-cell mitogen in human β-cells across several cell types
Representative images of DA-ZP1- or DA-FC-treated cells under the FITC channel measuring ZP1 release, DAPI staining, and the overlay. (E) Representative confocal images of dissociated human islets treated with DA-ZP1 followed by immunostaining for C-peptide. (F) Quantification of dispersed human islets treated with DA-ZP1 (n = 4)

Summary

Introduction

The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging. Multiple avenues in diabetes research and therapeutic development will benefit immensely from methods that selectively release small molecules into β-cells over other islet cells ex vivo or other cell-types in vivo.

Results

Conclusion