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

ABSTRACT: The loss of insulin-producing ?-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote ?-cell proliferation, protection, and imaging. However, the lack of ?-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in ?-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 ?-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to ?-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in ?-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 ?-cells.

SUBMITTER: Lee M 

PROVIDER: S-EPMC7146867 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature