Pancreas-Specific Delivery of β-Cell Proliferating Small Molecules.
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.
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.
Xueshi
X
Hao
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.
Qihui
Q
Jin
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.
Porino
P
Va
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.
Chun
C
Li
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.|California Institute of Biomedical Research, La Jolla, CA, 92037, USA.
Weijun
W
Shen
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA.
Bryan
B
Laffitte
The Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA. tyhwu@yahoo.com.
Tom Y-H
TY
Wu
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000378:metabolism*; D011724:Pyridazines / Q000737:chemistry; D011817:Rabbits; D053719:Tandem Mass Spectrometry; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014018:Tissue Distribution; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D004337:Drug Carriers; D011724:Pyridazines; D050493:Vesicular Monoamine Transport Proteins; C513630:aminopyridazine; C032811:dihydrotetrabenazine; D013747:Tetrabenazine
diabetes; drug delivery; imaging agents; tissue specificity; β-cell proliferation