Department of Liver Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
Institute of Hepatobiliary Diseases of Wuhan University, Transplant Centre of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Drug Deliv. 2021 Dec;28(1):2033-2043. doi: 10.1080/10717544.2021.1983072.
Triptolide (TPL) is a diterpenoid triepoxide with broad antitumor efficacy, while lack of mechanism of action, severe systemic toxicity, and poor water solubility of TPL limited its usage. To unveil the mechanism of action and improve the pharmaceutical properties of TPL, here we explored the molecular mechanism of TPL and then fabricated TPL-loaded membrane protein-chimeric liposomes (TPL@MP-LP) and tested its anticancer efficacy against hepatocellular carcinoma (HCC). CCK8 assay, colony formation assay, EdU assay, and flow cytometry were used to examine the activity of TPL. RNA sequence and gain-and-loss of function assays were used to explore the molecular mechanisms. TPL@MP-LP was characterized by size, zeta potential, polydispersity index, and transmission electron microscopy. Cellular uptake and cell viability assay were performed to evaluate the internalization and anticancer efficacy of TPL@MP-LP . Biodistribution and antitumor efficacy of TPL@MP-LP were evaluated on orthotopic HCC mice models. TPL robustly inhibited HCC cells by inducing cell proliferation arrest, apoptosis via the mitochondrial pathway, and necroptosis via RIPK1/RIPK3/MLKL signaling. TPL was successfully loaded into MP-LP, with a drug-loading capacity of 5.62 ± 0.80%. MP-LP facilitated TPL internalization and TPL@MP-LP exerted enhanced anticancer efficacy against Huh7 cells. TPL@MP-LP showed targeting ability to the tumor site. More importantly, TPL@MP-LP treatment suppressed tumor growth but showed minimal damage to liver and renal functions. TPL exerted anticancer effects on HCC via inducing cell proliferation arrest, apoptosis, and necroptosis, and the MP-LP might be a promising delivery strategy to improve the antitumor efficacy while mitigating toxicity of TPL for HCC therapy.
雷公藤红素（TPL）是一种具有广泛抗肿瘤功效的二萜三环氧化合物，但其作用机制不明、全身毒性严重、水溶性差，限制了其应用。为揭示 TPL 的作用机制并改善其药学性质，我们在此探索了 TPL 的分子机制，然后制备了载 TPL 的膜蛋白嵌合脂质体（TPL@MP-LP），并测试了其对肝细胞癌（HCC）的抗癌功效。CCK8 检测、集落形成检测、EdU 检测和流式细胞术用于检测 TPL 的活性。RNA 序列和功能获得和缺失实验用于探索分子机制。TPL@MP-LP 的粒径、Zeta 电位、多分散指数和透射电镜进行了表征。细胞摄取和细胞活力测定用于评估 TPL@MP-LP 的内化和抗癌功效。TPL@MP-LP 的体内分布和抗肿瘤功效在原位 HCC 小鼠模型中进行了评估。TPL 通过诱导细胞增殖停滞、线粒体途径诱导细胞凋亡和 RIPK1/RIPK3/MLKL 信号通路诱导细胞坏死来强烈抑制 HCC 细胞。TPL 成功载入 MP-LP，载药量为 5.62±0.80%。MP-LP 促进 TPL 的内化，TPL@MP-LP 对 Huh7 细胞表现出增强的抗癌功效。TPL@MP-LP 对肿瘤部位具有靶向能力。更重要的是，TPL@MP-LP 治疗抑制肿瘤生长，但对肝肾功能损伤最小。TPL 通过诱导细胞增殖停滞、凋亡和坏死发挥对 HCC 的抗癌作用，MP-LP 可能是一种有前途的给药策略，可提高抗肿瘤功效，同时减轻 TPL 对 HCC 治疗的毒性。
