Celastrol-Loaded Galactosylated Liposomes Effectively Inhibit AKT/c-Met-Triggered Rapid Hepatocarcinogenesis in Mice
Celastrol-Loaded Galactosylated Liposomes Effectively Inhibit AKT/c-Met-Triggered Rapid Hepatocarcinogenesis in Mice
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DOI：
10.1021/acs.molpharmaceut.9b00428
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发表时间：
2020-03-01
影响因子：
4.9
通讯作者：
Zheng, Guohua
中科院分区：
文献类型：
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作者：
Chen, Xinyan;Hu, Xianxian;Zheng, Guohua
我们之前的研究证明雷公藤红素是肝细胞癌（HCC）治疗的潜在候选者。但水溶性差和毒副作用可能限制其临床应用。为了克服这些缺点并优化其抗肿瘤功效，我们使用半乳糖修饰的1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-聚乙二醇开发了半乳糖基化脂质体来传递雷公藤红醇（C-GPL）。 C-GPL提高了雷公藤红醇的水溶性，并表现出高包封率、良好的血清稳定性和缓慢的药物释放特性。体外研究表明，C-GPL通过受体介导的内吞作用增加细胞对雷公藤红素的摄取，从而增强雷公藤红醇的细胞毒性和癌细胞凋亡。特别是，在通过水动力转染活化形式的 AKT 和 c-Met 建立的快速 HCC 小鼠模型中评估了 C-GPL 的体内抗肿瘤活性。与游离雷公藤红醇相比，C-GPL显着阻止肝脏重量增加，降低肝损伤生物标志物（谷草转氨酶和丙氨酸转氨酶）和HCC标志物（甲胎蛋白），并导致肝脏表面肿瘤消失。 C-GPL 改善的治疗效果可能归因于抑制 AKT 激活、诱导细胞凋亡和延缓细胞增殖。重要的是，C-GPL 对正常组织的毒性较低，不会导致小鼠体重严重减轻。综上所述，C-GPL 可能成为一种有前途的 HCC 治疗药物递送系统。
Our previous study proved that celastrol was a potential candidate for hepatocellular carcinoma (HCC) therapy. However, poor water solubility and toxic side effects may restrict its clinical application. To overcome these shortcomings and optimize its antitumor efficacy, we developed galactosylated liposomes using galactose-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) to deliver celastrol (C-GPL). C-GPL improved the water solubility of celastrol and exhibited high encapsulation efficiency, good stability in serum, and slow drug release profile. In vitro studies showed that C-GPL increased the cellular uptake of celastrol through receptor-mediated endocytosis, thereby enhancing celastrol cytotoxicity and cancer cell apoptosis. Particularly, in vivo antitumor activity of C-GPL was assessed in rapid HCC mouse models established via hydrodynamic transfection of the activated forms of AKT and c-Met. Compared to free celastrol, C-GPL significantly prevented liver weight gain, decreased liver damage biomarkers (glutamic-oxalacetic transaminase and alanine aminotransferase) and HCC marker (alpha-fetoprotein), and led to tumor disappearance on the liver surface. The improved therapeutic effect of C-GPL may be attributed to suppression of AKT activation, induction of apoptosis, and retardation of cell proliferation. Importantly, C-GPL exerted low toxicity to normal tissues without causing severe weight loss in mice. Taken together, C-GPL may become a promising drug delivery system for HCC treatment.