Abstract #669: Development of new tumor targeting 10B-carrier: Boron cluster-cyclic RGD pentapeptide conjugates for boron neutron capture therapy

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO A neutron capture reaction in boron [10B(n, \#945;)7Li] is, in principle, very effective in destroying tumors, providing that sufficient amount of 10B can be accumulated in the target tumor. However one of the major limitations in boron neutron capture therapy (BNCT) is insufficient and heterogeneous delivery of 10B from currently used 10B carriers, such as sodium mercaptoundecahydrododecaborate-10B (BSH) and L-4-boronophenylalanine-10B (BPA), into the target tumors. To augment the efficiency of BNCT, we developed new 10B carriers containing the Arg-Gly-Asp (RGD) motif which is the minimum recognition element for the \#945;v\#946;3 integrin. The \#945;v\#946;3 integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins. In this report, various boron cluster-cyclic RGD pentapeptide conjugates were synthesized and we analyzed their biodistribution and cytocidal effects of neutron irradiation to evaluate their usefulness in BNCT. The cyclo(-Arg-Gly-Asp-D-Phe-Lys-) and N -methyl analog, cyclo(-Arg-Gly-Asp-D-Phe-MeLys-) were synthesized as a tumor targeting moiety by Fmoc solid-phase method and conjugated to various boron clusters, such as carboranes and BSH, through alkyl amide linker chain. They were purified by RP-LC and identified by ESI-MS. We estimated their hydrophobicity by RP-TLC experiments and cytotoxicity of these compounds by MTT assay using HCT116 cells. All of the boron cluster-cyclic RGD pentapeptide conjugates are more hydrophobic than BSH. The IC50 values of BSH derivatives on HCT116 cells are less than those of carborane derivatives because of higher hydrophilicity. Biodistribution studies were carried out using C3H/He female mice bearing SCCVII tumors on both hind legs. At various time points after administration, mice were sacrificed and tumors and some organs were collected. The boron concentrations in these tissues were measured by ICP-AES. Based on these findings in the biodistribution study, we have a plan to select a suitable dosage and a time point for starting thermal neutron irradiation for BNCT. And then, we will examine the effects of the new 10B-carrier on tumor cells in vivo in comparison with BSH. Further, we are also going to evaluate some other new derivatives for improving effects in BNCT. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 669.