Zhou Lili, Du Yang, Shang Yating, Xiang Debiao, Xia Xinhua
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People's Republic of China.
The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410208, People's Republic of China.
Int J Nanomedicine. 2024 Dec 3;19:12975-12998. doi: 10.2147/IJN.S498099. eCollection 2024.
Modern pharmacological studies have demonstrated that although triptolide (TP) is effective against hepatocellular carcinoma, it has poor water solubility and more toxic side effects. In this study, we used triptolide (TP), a bioactive constituent in Hook F, as a model drug to develop a novel nano-liposome drug delivery system for the treatment of liver tumours.
We constructed a functionally-modified triptolide liposome (FA+TPP-TP-Lips) using the film-dispersion method and investigated its physicochemical properties, mitochondrial targeting of hepatic tumour cells, in vitro and in vivo anti-hepatic tumour activity and its mechanism.
The prepared FA+TPP-TP-Lips had a particle size of 99.28 ± 5.7 nm, a PDI of 0.20 ± 0.02, a zeta potential of 1.2 ± 0.08 mV, and an encapsulation rate of 74.37% ± 1.07%.FA+TPP-TP-Lips facilitates the cellular uptake of drug delivery systems and improves their targeted delivery to mitochondria. The results of cell efficacy showed that FA+TPP-TP-Lips significantly inhibited the growth of liver cancer cells, decreased mitochondrial membrane potential, and increased intracellular ROS, thus enhancing the highest apoptosis rate of liver cancer cells. The targeted liposomes (FA-TP-Lips, TPP-TP-Lips, and FA+TPP-TP-Lips) had some degree of inhibitory migration effect on Huh-7 cells relative to the unmodified TP-Lips. Studies on tumor-bearing mice demonstrated that FA+ TPP-TP-Lips effectively accumulated in tumor tissues and significantly inhibited the growth of subcutaneous tumors, achieving a tumor inhibition rate of 79.37%. FA+ TPP-TP-Lips demonstrated an enhanced anti-liver tumor effect and significantly mitigated the hepatotoxicity and systemic toxicity associated with TP.
In summary, the results of this study can provide a feasible solution for improving the mitochondrial targeting of nano-liposomes, and lay a foundation for further developing a novel nano targeting preparation of triptolide for the treatment of hepatocellular carcinoma.
现代药理学研究表明，雷公藤甲素（TP）虽对肝细胞癌有效，但水溶性差且毒副作用较大。在本研究中，我们以雷公藤甲素（TP）这一雷公藤中的生物活性成分作为模型药物，开发一种用于治疗肝肿瘤的新型纳米脂质体药物递送系统。
我们采用薄膜分散法构建了功能修饰的雷公藤甲素脂质体（FA+TPP-TP-Lips），并研究了其理化性质、对肝肿瘤细胞的线粒体靶向性、体内外抗肝肿瘤活性及其机制。
制备的FA+TPP-TP-Lips粒径为99.28±5.7nm，多分散指数（PDI）为0.20±0.02，zeta电位为1.2±0.08mV，包封率为74.37%±1.07%。FA+TPP-TP-Lips促进药物递送系统的细胞摄取，并改善其对线粒体的靶向递送。细胞药效学结果表明，FA+TPP-TP-Lips显著抑制肝癌细胞生长，降低线粒体膜电位，增加细胞内活性氧（ROS），从而提高肝癌细胞的最高凋亡率。相对于未修饰的TP-Lips，靶向脂质体（FA-TP-Lips、TPP-TP-Lips和FA+TPP-TP-Lips）对Huh-7细胞有一定程度的抑制迁移作用。对荷瘤小鼠的研究表明，FA+TPP-TP-Lips有效蓄积于肿瘤组织，显著抑制皮下肿瘤生长，肿瘤抑制率达79.37%。FA+TPP-TP-Lips显示出增强的抗肝肿瘤作用，并显著减轻与TP相关的肝毒性和全身毒性。
综上所述，本研究结果可为提高纳米脂质体的线粒体靶向性提供可行方案，为进一步开发用于治疗肝细胞癌的新型雷公藤甲素纳米靶向制剂奠定基础。
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