Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells

Diabetes is a hyperglycemic condition characterized by pancreatic beta-cell dysfunction and depletion. Whereas methods for monitoring beta-cell function in vivo exist, methods to deliver therapeutics to beta cells are lacking. We leveraged the rare ability of beta cells to concentrate zinc to preferentially trap zinc-binding molecules within beta cells, resulting in beta-cell-targeted compound delivery. We determined that zinc-rich beta cells and islets preferentially accumulated TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline) in a zinc-dependent manner compared with exocrine pancreas. Next, we asked whether appending a zinc-chelating moiety onto a beta-cell replication-inducing compound was sufficient to confer preferential beta-cell accumulation and activity. Indeed, the hybrid compound preferentially accumulated within rodent and human islets in a zinc-dependent manner and increased the selectivity of replication-promoting activity toward beta cells. These data resolve the fundamental question of whether intracellular accumulation of zinc-chelating compounds is influenced by zinc content. Furthermore, application of this principle yielded a proof-of-concept method for beta-cell-targeted drug delivery and bioactivity.