Tumor vasculature-targeted 10B delivery by an Annexin A1-binding peptide boosts effects of boron neutron capture therapy
Tohru Yoneyama, Shingo Hatakeyama, Mihoko Sutoh Yoneyama, Taku Yoshiya, Tsuyoshi Uemura, Takehiro Ishizu, Minoru Suzuki, Shingo Hachinohe, Shintaro Ishiyama, Motohiro Nonaka, Michiko N. Fukuda, Chikara Οhyama
Abstract
Abstract Background p -Boronophenylalanine ( 10 BPA) is a powerful 10 B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10 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 10 BPA or borocaptate sodium ( 10 BSH). Methods (1) IF7 conjugates of either 10 B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10 B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7- 10 B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice. Results Intravenous injection of IF7C conjugates of either 10 B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10 B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10–20 mg/kg) doses of IF7- 10 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. Conclusions We conclude that IF7 serves as an efficient 10 B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.