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

Cell Chem Biol. 2019 Feb 21;26(2):213-222.e6. doi: 10.1016/j.chembiol.2018.10.019. Epub 2018 Dec 6.

Abstract

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

Keywords: chelation; diabetes; islet; targeted compound delivery; targeting; tissue selectivity; zinc; β cell; β-cell regeneration; β-cell-replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / analysis
  • Aminoquinolines / chemistry
  • Aminoquinolines / metabolism
  • Animals
  • Chelating Agents / chemistry*
  • Chelating Agents / metabolism
  • Chromatography, High Pressure Liquid
  • Dithizone / chemistry
  • Dithizone / metabolism
  • Ethylenediamines / analysis
  • Ethylenediamines / chemistry
  • Ethylenediamines / metabolism
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Tandem Mass Spectrometry
  • Tosyl Compounds / analysis
  • Tosyl Compounds / chemistry
  • Tosyl Compounds / metabolism
  • Zinc / chemistry*

Substances

  • Aminoquinolines
  • Chelating Agents
  • Ethylenediamines
  • Protein Kinase Inhibitors
  • Tosyl Compounds
  • Dithizone
  • N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Zinc
  • N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine