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Pancreas-Specific Delivery of β-Cell Proliferating Small Molecules

Hao, Xueshi and Jin, Qihui and Va, Porino and Li, Chun and Shen, Weijun and Laffitte, Bryan and Wu, Tom (2016) Pancreas-Specific Delivery of β-Cell Proliferating Small Molecules. ChemMedChem, 11 (11). pp. 1129-1132. ISSN 1860-7187

Abstract

Our research groups recently described a series of small-molecule inducers of β-cell proliferation that could be used to increase β-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 β-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The β-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). In vivo 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 β-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a β-cell imaging agent.

Item Type: Article
Keywords: diabetes drug delivery imaging agents tissue specificity β-cell proliferation
Date Deposited: 21 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/28069

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