title: Synthesis and evaluation of cyclic RGD-boron cluster conjugates to develop tumor-selective boron carriers for boron neutron capture therapy.
abstract: 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 αvβ3 is an attractive target for anti-tumor drug delivery because of its specific expression in proliferating endothelial and tumor cells of various origins. We, therefore, selected a c(RGDfK) moiety recognizing αvβ3 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 αvβ3-positive U87MG and SCCVII cells demonstrated the high binding affinity of conjugates to integrin αvβ3 (IC(50)=0.19-2.66 μM). 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.
authors.affiliation: Laboratory of Medicinal & Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Sadaaki
authors.initials: S
authors.lastname: Kimura
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Harada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Okuda
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D001895:Boron / Q000737:chemistry; D016754:Boron Neutron Capture Therapy; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D007275:Injections, Intravenous; D051379:Mice; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D001895:Boron