Nishimura Kai, Tanaka Shota, Miura Kazuki, Okada Satoshi, Suzuki Minoru, Nakamura Hiroyuki
School of Life Science and Technology, Institute of Science Tokyo, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Laboratory for Chemistry and Life Science, Institute of Integrated Research, Institute of Science Tokyo, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
ACS Omega. 2024 Dec 18;9(52):51631-51640. doi: 10.1021/acsomega.4c09388. eCollection 2024 Dec 31.
A critical challenge in boron neutron capture therapy (BNCT) is expanding its effectiveness through the development of novel boron agents with different mechanisms of action than the approved drug 4-borono-l-phenylalanine (BPA). In this study, we developed a small molecule boron carrier, biotinyl--dodecaborate conjugate with an iodophenyl moiety (BBC-IP), incorporating biotin as a ligand for biotin receptors overexpressed in various cancer cells, alongside an albumin ligand and boron source. BBC-IP exhibited high water solubility, minimal cytotoxicity, and superior cellular uptake compared to BPA in both human and mouse cancer cells. Biodistribution studies revealed that BBC-IP achieved enhanced tumor accumulation (9.7 μg [B]/g, 3 h) in mouse colon tumors, surpassing BPA's accumulation levels (7.2 μg [B]/g, 3 h) at a dose of 15 mg [B]/kg. However, despite this improved tumor accumulation, BPA demonstrated superior BNCT efficacy. The intracellular localization of boron agents in tumor cells revealed that BPA localized throughout the cell, whereas BBC-IP localized mainly in the cytoplasm. These results indicate the intratumoral localization, as well as tumor accumulation are critical for the efficacy of novel BNCT agents.
硼中子俘获疗法（BNCT）面临的一项关键挑战是，通过开发作用机制与已获批药物4-硼基-L-苯丙氨酸（BPA）不同的新型硼剂来提高其疗效。在本研究中，我们开发了一种小分子硼载体，即带有碘苯基部分的生物素基-十二硼酸盐偶联物（BBC-IP），它将生物素作为在各种癌细胞中过表达的生物素受体的配体，同时还含有白蛋白配体和硼源。与BPA相比，BBC-IP在人和小鼠癌细胞中均表现出高水溶性、最小细胞毒性和优异的细胞摄取能力。生物分布研究表明，在15 mg [B]/kg的剂量下，BBC-IP在小鼠结肠肿瘤中的肿瘤蓄积量增强（3小时时为9.7 μg [B]/g），超过了BPA的蓄积水平（3小时时为7.2 μg [B]/g）。然而，尽管肿瘤蓄积有所改善，但BPA显示出更优异的BNCT疗效。肿瘤细胞中硼剂的细胞内定位显示，BPA分布于整个细胞，而BBC-IP主要定位于细胞质。这些结果表明，肿瘤内定位以及肿瘤蓄积对新型BNCT剂的疗效至关重要。
