Acid-sensitive polymeric vector targeting to hepatocarcinoma cells via glycyrrhetinic acid receptor-mediated endocytosis.

Liver cancer is one of the top death causing cancers, traditional treatments have not settled for the requirement of patients. In this work, a smart acid-responsive micelle based on glycyrrhetinic acid modified chitosan-polyethyleneimine-4-Hydrazinobenzoic acid-doxorubicin (GA-CS-PEI-HBA-DOX) was synthesized for targeted delivery of DOX to liver cancer. A dual pH-sensitive and receptor-mediated strategy has been exploited to enhance the delivery efficiency. The micelle possesses positive charges under pH 6.8 and can be turned into negative charges above pH 7.0, which help to be accumulated in tumor tissues (pH 6.0-7.0). In the intracellular environment (pH 4.5-6.5) of tumor cells, the pH-sensitive hydrazone bonds between DOX and GA-CS-PEI-HBA would break and release as much as 90.3% of the encapsulated payloads in 48 h. In addition, GA was modified to improve the targeting abilities. The micelles exhibited high lethality to HepG2 cells while showed much lower cytotoxicity to HUVEC cells. With high drug-loading capacity and the targeted release ability, the GA-CS-PEI-HBA-DOX micelle might be employed as a promising candidate for targeted cancer treatment.