Boron neutron capture therapy using dodecaborated albumin conjugates with maleimide is effective in a rat glioma model

• Published in: Investigational new drugs 2022-04, Vol.40 (2), p.255-264
• Main Authors: Kashiwagi, Hideki, Kawabata, Shinji, Yoshimura, Kohei, Fukuo, Yusuke, Kanemitsu, Takuya, Takeuchi, Koji, Hiramatsu, Ryo, Nishimura, Kai, Kawai, Kazuki, Takata, Takushi, Tanaka, Hiroki, Watanabe, Tsubasa, Suzuki, Minoru, Miyatake, Shin-Ichi, Nakamura, Hiroyuki, Wanibuchi, Masahiko
• Format: Article
• Language: English
• Subjects: Albumin; Albumins; Animal models; Animals; Biological effects; Boron; Boron - therapeutic use; Boron compounds; Boron Compounds - therapeutic use; Boron Neutron Capture Therapy - methods; Brain cancer; Brain Neoplasms - drug therapy; Brain tumors; Conjugates; Drug delivery; Drug delivery systems; Glioma; Glioma - pathology; Humans; Intravenous administration; Irradiation; Maleimides; Medicine; Medicine & Public Health; Neutron irradiation; Neutrons; Nuclear capture; Oncology; Pharmacology/Toxicology; Preclinical Studies; Prolongation; Rats; Serum albumin; Statistical analysis; Survival; Therapy; Tissue Distribution; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01201-7

Summary Introduction  Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing.  Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo -dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion  MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.