Hepatocellular carcinoma is one of the severest malignant tumors with high mortality in patients. Sorafenib, a first-line drug, is extensively used for treating hepatocellular carcinoma. However, the efficacy of this chemotherapy treatment is limited in clinically due to the obstacles including rapid drug clearance from blood circulation, tumor drug resistance, and obvious adverse effects. To address those problems mentioned above, pH-sensitive hyaluronic acid nanoparticles were synthesized by crosslinking hyaluronic acid with cisplatin and encapsulating with sorafenib. The obtained HA@cis-Pt@SF showed prolonged circulation time and high accumulation rate. Besides, the pH-sensitive property of HA@cis-Pt@SF owing to chelation interactions between cisplatin and hyaluronic acid guaranteed the major release of loaded drugs in tumor sites, avoiding untimely release. Moreover, sorafenib and cisplatin, two chemotherapeutic drugs based on different antitumor mechanisms, exerted synergistic tumor-killing effects after valid tumor accumulation and pH-responsive release in cancer cells. Above all, the enhanced antitumor efficacy and reduced cytotoxicity of HA@cis-Pt@SF make it a desirable candidate for chemotherapy of hepatocellular carcinoma.
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