Tumor vasculature-targeted 10 B delivery by an Annexin A1-binding peptide boosts effects of boron neutron capture therapy

p-Boronophenylalanine ( BPA) is a powerful B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated BPA or borocaptate sodium ( BSH). (1) IF7 conjugates of either B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7- B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice. Intravenous injection of IF7C conjugates of either B drugs into MBT2 bladder tumor-bearing mice promoted rapid B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7- B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes. We conclude that IF7 serves as an efficient B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.