厦门大学等人的研究开发出了新型光敏剂黄连素衍生物B12通过线粒体-细胞核序列靶向诱导结直肠癌癌症细胞凋亡并抑制HIF-1α表达。这一研究成果于2026年1月20日发表在国际顶尖学术期刊《中国药理学报》上。

该课题组研究人员之前对植物源生物碱小檗碱进行了构效关系（SAR）研究，发现其衍生物B12不仅能显著增强抗肿瘤功效，还能提高水溶性和生物利用度。在本研究中，研究小组表征了B12的光动力特性，研究了其抗癌机制，并评估了B12在异种移植物肿瘤模型中的光动力治疗效果和生物安全性。小组发现B12是一种新型光敏剂，没有ACQ效应，具有I型和II型光动力学活性，在常氧和缺氧条件下都能产生大量活性氧（ROS）。

此外，B12 (12.5, 25μM)通过抑制AKT/mTOR信号通路和下调缺氧诱导因子HIF-1α的表达，显著增强其对缺氧微环境下RKO和HCT116细胞的治疗作用。在RKO细胞中，B12 (2μM)在光激活后表现出动态的双细胞器靶向特性：首先诱导线粒体膜电位崩溃，然后转移到核仁并与DNA结合。它通过缩小单线态和三重态的能隙来提高系统间交叉（ISC）效率，从而增加ROS的产生并破坏DNA的完整性。在移植了B16细胞的小鼠中，瘤内注射B12 (5Mg /kg)，然后是10每日最小光照射9天可显著抑制肿瘤生长，生物安全性良好。综上所述，小分子B12同时具有I型和II型光动力活性、动态细胞器靶向和缺氧适应特性。本研究可为耐缺氧小分子光敏剂的研究和设计提供参考，突破光动力治疗的临床瓶颈。

研究人员表示，光动力疗法（PDT）具有高时空选择性和无创性等优点，但由于肿瘤微环境缺氧，传统光敏剂存在聚集诱导猝灭（ACQ）、靶向能力不足、全身毒性等缺陷，其临床应用仍受到限制。

附：英文原文

Title: A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting

Author: Pei, Wen-bin, Lei, Zi-yu, Xie, Fu-quan, Chen, Peng, Su, Yong-cheng, Qin, Yu-shan, Li, Jiang-quan, Shen, Qian-wen, Ma, Miao-miao, Gao, Chun-yi, Zhu, Jia-chen, Xu, Ya-jie, Zhang, Kai-yue, Zhang, Wen-qing, Zhang, Yan-dong, Hu, Tian-hui, Xu, Bei-bei

Issue&Volume: 2026-01-20

Abstract: Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of reactive oxygen species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the AKT/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5mg/kg) followed by 10min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.

DOI: 10.1038/s41401-025-01728-y

Source: https://www.nature.com/articles/s41401-025-01728-y