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

ABSTRACT: Diabetes is a hyperglycemic condition characterized by pancreatic ?-cell dysfunction and depletion. Whereas methods for monitoring ?-cell function in vivo exist, methods to deliver therapeutics to ? cells are lacking. We leveraged the rare ability of ? cells to concentrate zinc to preferentially trap zinc-binding molecules within ? cells, resulting in ?-cell-targeted compound delivery. We determined that zinc-rich ? 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 ?-cell replication-inducing compound was sufficient to confer preferential ?-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 ? 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 ?-cell-targeted drug delivery and bioactivity.

SUBMITTER: Horton TM 

PROVIDER: S-EPMC6386607 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature