Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 5, Pages 1721-1728Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.01.020
Keywords
Integrin alpha v beta 3; Boron neutron capture therapy (BNCT); o-Carborane; Cyclic RGD
Funding
- Saijiro Endo Memorial Foundation for Science Technology
- Japan Science Society [19621]
- Japan Society for the Promotion of Science [19590102]
- Grants-in-Aid for Scientific Research [23300348, 19590102] Funding Source: KAKEN
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Boron-containing agents play a key role in successful boron neutron capture therapy (BNCT). Icosahedral boron cluster-Arg-Gly-Asp (RGD) peptide conjugates were designed, synthesized, and evaluated for the biodistribution to develop tumor-selective boron carriers. Integrin alpha v beta 3 is an attractive target for antitumor drug delivery because of its specific expression in proliferating endothelial and tumor cells of various origins. We, therefore, selected a c(RGDfK) moiety recognizing alpha v beta 3 as an active tumor-targeting device to conjugate with icosahedral boron-10 clusters, disodium mercaptododecaborate (BSH) or o-carborane as a thermal neutron-sensitizing unit. Preparation of o-carborane derivatives involved microwave irradiation, and resulted in high yields in a short time. An in vitro cell adhesion assay on alpha v beta 3-positive U87MG and SCCVII cells demonstrated the high binding affinity of conjugates to integrin alpha v beta 3 (IC50 = 0.19-2.66 mu M). Biodistribution experiments using SCCVII-bearing mice indicated that GPU-201 showed comparable tumor uptake and a significantly longer retention in tumors compared with BSH. These results suggest that GPU-201 is a promising candidate for use in BNCT. (C) 2011 Elsevier Ltd. All rights reserved.
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