Inhibition of hepatocellular carcinoma progression by methotrexate-modified pH-sensitive sorafenib and Schisandrin B micelles.

Abstract

Introduction: Due to the lack of specific symptoms, hepatocellular carcinoma is often detected in advanced stages. However, pharmacological systemic therapy, a common clinical treatment for advanced hepatocellular carcinoma, 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. Methods: 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 vitro. 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. Results: 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 hepatocellular carcinoma cells with high expression of folate receptor in vitro and in vivo. Moreover, MTX-SOR/SchB micelles could inhibit the proliferation, invasion and metastasis of HCC in vitro and in vivo and promote apoptosis. MTX-SOR/SchB micelles also show good biosafety. Conclusion: In conclusion, MTX-SOR/SchB micelles can effectively enhance the therapeutic effect of hepatocellular carcinoma, reduce systemic toxicity of drugs, which is expected to be used in clinical treatment. .