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journal contribution
posted on 2020-03-26, 14:34authored byMiseon Lee, Basudeb Maji, Debasish Manna, Sevim Kahraman, Ruth M. Elgamal, Jonnell Small, Praveen Kokkonda, Amedeo Vetere, Jacob M. Goldberg, Stephen J. Lippard, Rohit N. Kulkarni, Bridget K. Wagner, Amit Choudhary
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.