Synthesis and in vivo murine evaluation of Na_4[1-( 1 '-B_(10)H_9)-6- SHB_(10)H_8] as a potential agent for boron neutron capture therapy

摘要

Reaction of the normal isomer of [B_(20)H_(18)]~(2-) and the protected thiol anion, [SC(O)OC(CH_3)_3]~-, produces an unexpected isomer of [B_(20)H_(17)SC (O) OC(CH_3)_3]~(4-) directly and in good yield. The isomer produced under mild conditions is characterized by an apical-apical boron atom intercage connection as well as the location of the thiol substituent on an equatorial belt adjacent to the terminal boron apex. Although the formation of this isomer from nucleophilic attack of the normal isomer of [B_20)H_(18)]~(2-) has not been reported previously, the isomeric assignment has been unam- biguously confirmed by one-dimensional and two-dimensional ~(11)B NMR spectroscopy. Deprotection of the thiol substituent under acidic conditions produces a protonated intermediate, [B_(20)H_(18)SH]~(3-), which can be deprotonated with a suitable base to yield the desired product, [B_(20)H_(17)SH]~(4-). The sodium salt of the resulting [B_(20)H_(17)SH]~(4-) ion has been encapsulated in small, unilamellar liposomes, which are capable of delivering their contents selectively to tumors in vivo, and investigated as a potential agent for boron neutron capture therapy. The biodistribution of boron was determined after intravenous injection of the liposomal suspension into BALB/c mice bearing EMT6 mammary adenocarcinoma. At low injected doses, the tumor boron concentration increased throughout the time-course experiment, resulting in a maximum observed boron concentration of 46.7 #mu#g of B per g of tumor at 48 h and a tumor to blood boron ratio of 7.7. The boron concentration obtained in t