Details

Autor(en) / Beteiligte

• Hao, Xueshi
• Jin, Qihui
• Va, Porino
• Li, Chun
• Shen, Weijun
• Laffitte, Bryan
• Wu, Tom Y-H

Titel

Pancreas-Specific Delivery of [beta]-Cell Proliferating Small Molecules

Ist Teil von

• ChemMedChem, 2016-06, Vol.11 (11), p.1129

Ort / Verlag

Weinheim: Wiley Subscription Services, Inc

Erscheinungsjahr

2016

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Our research groups recently described a series of small-molecule inducers of [beta]-cell proliferation that could be used to increase [beta]-cell mass. To mitigate the risk of nonspecific proliferation of other cell types, we devised a delivery strategy built on the tissue specificity observed in the experimental [beta]-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The [beta]-cell proliferator agent aminopyrazine (AP) was covalently linked with (+)-DTBZ to afford conjugates that retain both the proliferation activity and binding affinity for vesicular monoamine transporter-2 (VMAT2). Invivo mouse tissue distribution studies of a prototypical AP-DTBZ conjugate showed 15-fold pancreas exposure over plasma. Tissue-to-plasma ratios in liver and kidneys were two- and five-fold, respectively. This work is the first demonstration of enhanced delivery of [beta]-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a [beta]-cell imaging agent.