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

Abstract

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 evaluatedin 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. 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 receptorin vitroandin vivo. Moreover, MTX-SOR/SchB micelles could inhibit the proliferation, invasion and metastasis of HCCin vitroandin vivoand 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.