Yan Yu-Hui, Kong Liang, Lu Ying-Bo, Li Si-Yang, Yan Ai-Wen, Song Yue-Wen, Huang Zi-Han, Zhu Hao-Nan
School of Parmacy, Jiangsu Food and pharmaceutical Science College, Huai'an, Jiangsu 223003, People's Republic of China.
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, People's Republic of China.
Biomed Mater. 2024 Dec 13;20(1). doi: 10.1088/1748-605X/ad9aef.
Due to the lack of specific symptoms, hepatocellular carcinoma (HCC) is often detected in advanced stages. However, pharmacological systemic therapy, a common clinical treatment for advanced HCC, is prone to serious toxic side effects. To address these issues, we designed a pH-sensitive sorafenib and schisandrin B micelle modified by methotrexate (MTX-SOR/SchB micelles), a nanosystem that combines the advantages of targeted delivery and pH sensitivity, and is capable of improving drug bioavailability and mitigating drug toxic side effects. Firstly, we characterized the physical and chemical properties of micelles, including particle size, Zeta potential, encapsulation efficiency, pH sensitivity and stability. Hepa1-6 cells and fluorescence imaging were used to investigate the targeting ability of MTX-SOR/SchB micelles. Anti-hepa1-6 cell proliferation, invasion, migration, and pro-apoptotic effects were evaluated. In addition, HCC tumor-bearing mouse and lung metastasis mouse models were established to investigate the anti-HCC ability of MTX-SOR/SchB micelles, and finally their biological safety was evaluated. We found that the particle size of MTX-SOR/SchB micelles was uniformly distributed, could effectively encapsulation of the drug, had low leakage rate, sensitive pH response, and perfect stability. And MTX-SOR/SchB micelles could target HCC cells with high expression of folate receptorand. Moreover, MTX-SOR/SchB micelles could inhibit the proliferation, invasion and metastasis of HCCandand promote apoptosis. MTX-SOR/SchB micelles also show good biosafety. In conclusion, MTX-SOR/SchB micelles can effectively enhance the therapeutic effect of HCC, reduce systemic toxicity of drugs, which is expected to be used in clinical treatment.
由于缺乏特异性症状，肝细胞癌（HCC）往往在晚期才被发现。然而，作为晚期HCC常见的临床治疗方法，药物全身治疗容易产生严重的毒副作用。为了解决这些问题，我们设计了一种由甲氨蝶呤修饰的pH敏感型索拉非尼和五味子醇甲胶束（MTX-SOR/SchB胶束），这是一种结合了靶向递送和pH敏感性优势的纳米系统，能够提高药物生物利用度并减轻药物毒副作用。首先，我们对胶束的物理化学性质进行了表征，包括粒径、Zeta电位、包封率、pH敏感性和稳定性。利用Hepa1-6细胞和荧光成像研究了MTX-SOR/SchB胶束的靶向能力。评估了其对Hepa1-6细胞增殖、侵袭、迁移的抑制作用以及促凋亡作用。此外，建立了HCC荷瘤小鼠和肺转移小鼠模型来研究MTX-SOR/SchB胶束的抗HCC能力，最后评估了它们的生物安全性。我们发现MTX-SOR/SchB胶束粒径分布均匀，能有效包封药物，泄漏率低，pH响应敏感，稳定性良好。并且MTX-SOR/SchB胶束能够靶向叶酸受体高表达的HCC细胞。此外，MTX-SOR/SchB胶束能够抑制HCC的增殖、侵袭和转移并促进细胞凋亡。MTX-SOR/SchB胶束还表现出良好的生物安全性。综上所述，MTX-SOR/SchB胶束能够有效增强HCC的治疗效果，降低药物的全身毒性，有望用于临床治疗。
