Dual - functional cRGD/pH - sensitive liposomes loaded with sorafenib: a novel therapeutic approach for hepatocellular carcinoma

Background Sorafenib, a first-line treatment for advanced hepatocellular carcinoma (HCC), is severely limited by its low oral bioavailability, lack of tumor specificity, and dose-limiting systemic adverse effects. Nanocarrier-based delivery systems, particularly liposomes, offer a promising strategy to overcome these limitations. Methods We developed a multifunctional liposomal system co-modified with a cyclic RGD (cRGD) peptide and pH-sensitive components (cholesteryl hemisuccinate, CHEMS) for sorafenib delivery (cRGD-pH-Lipo/Sor). The physicochemical properties, drug release profile, stability, and biosafety of this formulation were thoroughly characterized. Its targeting efficiency, cellular uptake, and antitumor efficacy were evaluated in both in vitro (Huh7 and HepG2 cells) and in vivo (Huh7-xenograft nude mice) models using techniques including HPLC, fluorescence imaging, CCK-8 and in vivo imaging system (IVIS). Results The optimized cRGD-pH-Lipo/Sor exhibited a uniform particle size distribution (116.73 ± 1.07 nm, polydispersity index of 0.224 ± 0.0017), negative zeta potential (−22.2 ± 3.50 mV), high encapsulation efficiency (84.1%), and a desirable pH-responsive drug release profile (cumulative release: 73.2% at pH 5.0% vs. 38.4% at pH 7.4). In vitro , cRGD-pH-Lipo/Sor demonstrated significantly enhanced cellular uptake in HCC cells compared to free sorafenib and non-targeted liposomes, attributable to cRGD-mediated active targeting and pH-triggered release. In vivo imaging and biodistribution studies confirmed the superior tumor accumulation of cRGD-pH-Lipo. Most importantly, in a xenograft mouse model, cRGD-pH-Lipo/Sor achieved the most potent tumor growth inhibition without inducing significant systemic toxicity, as evidenced by body weight monitoring, serum biochemical analysis, and histopathological examination. Conclusion The cRGD-modified, pH-sensitive liposomal platform effectively addresses key pharmacological drawbacks of sorafenib. It enhances tumor-targeted delivery, promotes intracellular drug release, and significantly improves the therapeutic index, presenting a promising novel strategy for the systemic treatment of advanced HCC.