Novel glycyrrhetinic acid conjugated pH-sensitive liposomes for the delivery of doxorubicin and its antitumor activities

Over the last few decades pH-sensitive drug delivery systems have been successfully developed for the treatment of cancers by improving the therapeutical effect. In this study, a novel pH-sensitive conjugate glycyrrhetinic acid-polyethylene glycol-Schiff bond-cholesterol (GPSC) has been synthesized successfully and used to construct doxorubicin (DOX)-loaded liposomes (GPSLP/DOX) with both pH-sensitive features and active targeting ability. DOX was incorporated into liposomes using a thin-film hydration method with a relatively high encapsulation efficiency (EE%) and drug loading content (LC%). Physicochemical characteristics, in vitro release behavior, cellular toxicity and cellular uptake, in vivo biodistribution as well as in vivo antitumor activities of GPSLP/DOX were investigated. GPSLP/DOX showed significantly pH-sensitive features in the in vitro release assay. All the blank liposomes were nontoxic in the in vitro cytotoxicity assay. In the MTT assay, GPSLP/DOX showed the highest cell cytotoxicity among all the groups. A cellular uptake study revealed that GPSLP/DOX could be taken up efficiently via receptor-mediated endocytosis and pH-responsive drug release of DOX into cytoplasm, which resulted in a higher cytotoxicity and therapeutical effect. An in vivo NIR fluorescence image study showed that GPSLP/DOX could specifically accumulate in the liver and tumor sites via receptor mediated endocytosis. In vivo antitumor activity results showed that this novel GPSLP/DOX could significantly inhibit tumor growth and prolong survival time due to its pH-responsive behaviour and GA-mediated endocytosis, resulting in a lower systematic toxicity and higher therapeutical effect. All these results confirm that this GA-mediated pH-sensitive GPSLP/DOX is a novel nanocarrier for the delivery of the antitumor agent DOX to reach higher toxicity effects against tumor tissue.