Wu Yang, Wang Menglan, Wang Yifan, Bu Fangtian, Yang Yuchun, Dong Heng, Zhang Zhengguo, Zhang Shanshan, Wu Zhenglong, Zhang Xiaoting, Chen Jianxiang, Han Bingnan
Zhejiang provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Laboratory of Antiallergy Functional Molecules, College of Life Sciences and Medicine, Zhejiang SciTech University, Hangzhou 310018, China.
School of Pharmacy and Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
Mol Pharm. 2025 Jul 7;22(7):3922-3934. doi: 10.1021/acs.molpharmaceut.5c00186. Epub 2025 Jun 9.
Actinomycin X2 (Act.X2), an analog of actinomycin D produced by marine-derived actinomycete , has shown promising antitumor activity. This study attempted to improve the delivery efficiency of Act.X2 through a targeted approach. We developed a folate (FA)-modified, Act.X2-loaded liposomal system (FA-Act.X2-Lips) to enhance its targeting specificity and antitumor efficacy against hepatocellular carcinoma (HCC). FA-Act.X2-Lips exhibited a uniform spherical morphology, an average particle size of approximately 139.85 nm, and an encapsulation efficiency of around 88.34%. Cytotoxicity assays demonstrated that FA-Act.X2-Lips have significantly higher cytotoxicity against HCCLM3 cells compared with the unmodified Act.X2-Lips. Additionally, an orthotopic HCC model in mice was established, and tail vein injections of FA-Act.X2-Lips were administered to study targeted drug delivery. Both in vitro targeting studies and in vivo fluorescent imaging assays demonstrated that FA-modified liposomes enhanced tumor-targeting efficiency. In terms of antitumor activity, FA-Act.X2-Lips significantly inhibited tumor growth in HCCLM3 tumor-bearing mice, compared with the free Act.X2 and unmodified Act.X2-Lips, while effectively inducing tumor cell apoptosis without notable toxicity to healthy tissues. The low toxicity profile of FA-Act.X2-Lips addresses a critical clinical limitation of conventional actinomycin-based therapies. These results suggest that FA-Act.X2-Lips hold a therapeutic potential for HCC treatment.
放线菌素X2（Act.X2）是一种由海洋放线菌产生的放线菌素D类似物，已显示出有前景的抗肿瘤活性。本研究试图通过靶向方法提高Act.X2的递送效率。我们开发了一种叶酸（FA）修饰的、负载Act.X2的脂质体系统（FA-Act.X2-Lips），以增强其对肝细胞癌（HCC）的靶向特异性和抗肿瘤疗效。FA-Act.X2-Lips呈现出均匀的球形形态，平均粒径约为139.85 nm，包封率约为88.34%。细胞毒性试验表明，与未修饰的Act.X2-Lips相比，FA-Act.X2-Lips对HCCLM3细胞具有显著更高的细胞毒性。此外，建立了小鼠原位HCC模型，并通过尾静脉注射FA-Act.X2-Lips来研究靶向药物递送。体外靶向研究和体内荧光成像试验均表明，FA修饰的脂质体提高了肿瘤靶向效率。在抗肿瘤活性方面，与游离Act.X2和未修饰的Act.X2-Lips相比，FA-Act.X2-Lips显著抑制了荷HCCLM3肿瘤小鼠肿瘤的生长，同时有效诱导肿瘤细胞凋亡，而对健康组织无明显毒性。FA-Act.X2-Lips的低毒性解决了传统基于放线菌素疗法的一个关键临床局限性。这些结果表明，FA-Act.X2-Lips在HCC治疗方面具有治疗潜力。
