Tohru Yoneyama1,2, Shingo Hatakeyama2, Mihoko Sutoh Yoneyama3, Taku Yoshiya4, Tsuyoshi Uemura4, Takehiro Ishizu4, Minoru Suzuki5, Shingo Hachinohe6, Shintaro Ishiyama7, Motohiro Nonaka8, Michiko N Fukuda9, Chikara Ohyama10. 1. Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, 036-8562, Japan. 2. Department of Urology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, 036-8562, Japan. 3. Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, 90 Kozawa Yamazaki, Hirosaki, 036-8243, Japan. 4. Peptide Institute Inc., 7-2-9 Saito-Asagi, Osaka, Ibaraki, 567-0085, Japan. 5. Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science (KURNS), Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan. 6. Aomori Prefecture Quantum Science Center (QSC), 2-190 Omotedate, Obuchi, Rokkasho-mura, Kamikita-gun, 039-3212, Japan. 7. Faculty of Science and Technology, Hirosaki University Graduate School of Science and Technology, 1-Bunkyo-cho, Hirosaki, 036-8562, Japan. 8. Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. 9. Tumor Microenvironment and Cancer Immunology Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA. 10. Department of Urology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, 036-8562, Japan. coyama@hirosaki-u.ac.jp.
Abstract
BACKGROUND: p-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA 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 10BPA or borocaptate sodium (10BSH). METHODS: (1) IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-10B 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 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7-10B 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 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.
BACKGROUND:p-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA 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 10BPA or borocaptate sodium (10BSH). METHODS: (1) IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-10B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/Hemice and YTS-1 tumor bearing nude mice. RESULTS: Intravenous injection of IF7C conjugates of either 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7-10B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of humanYTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes. CONCLUSIONS: We conclude that IF7 serves as an efficient 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.