Cell-penetrating corosolic acid liposome as a functional carrier for delivering chemotherapeutic drugs.

Corosolic acid (CA), a natural pentacyclic triterpenoid, exhibits antitumor and synergistic therapy effect with chemotherapeutic drugs mainly through inhibiting STAT3 activation. In this study, it is found that CA possesses cholesterol-like properties in liposome by regulating membrane phase behavior to form stable cholesterol-free CA liposomes (CALP). Compared with traditional cholesterol liposomes (CHOLP), CALP exhibit stronger membrane fusion and higher cellular uptake, and other functions including inhibition of STAT3 activation and suppression of the recruitment of macrophages to tumor microenvironment. Therefore, CALP is used as a functional carrier, and doxorubicin-loaded CALP (DOX/CALP) based on PEGylated liposomal doxorubicin (DOXIL) are prepared by replacing its cholesterol with CA. The physicochemical properties and biological activities are compared with those of doxorubicin-loaded cholesterol liposomes (DOX/LP). Both DOX/CALP and DOX/LP possess approximately similar physical properties and exhibit high stability and low drug leakage as shown by the published data of DOXIL. Nevertheless, it is noteworthy that DOX/CALP displays higher in vitro cellular uptake and tumor spheroid permeation along with stronger cytotoxicity against tumor cells than DOX/LP. Despite DOX/CALP has the same PK parameters, normal tissue biodistribution, and safety profile as DOX/LP, the results of an in vivo study in 4T1-bearing mice indicate that the DOX/CALP treatment group exhibit higher tumor accumulation, more significant tumor growth inhibition, and longer life span than the DOX/LP group. Overall, DOX/CALP is a representative example of CA-doped liposomes, suggesting that CALP as a functional drug carrier for solving low efficacy of present liposomal drugs might have promising application potential. STATEMENT OF SIGNIFICANCE: An original drug delivery nanocarrier, corosolic acid liposome (CALP), was developed in this study. It was found that CA possesses cholesterol-like function to regulate phospholipid membrane phase behavior. By replacing the cholesterol with CA, the liposomes were converted into high cellular uptake carriers, possessing anti-inflammatory activity and synergism with chemotherapeutic drugs. The variability of CALP formulations enabled to deliver therapeutic agents. The use of CALP to deliver doxorubicin not only significantly enhanced the therapeutic efficacy compared with the classic PEGylated liposomal doxorubicin, but also maintained the improved safety. Because CALP can be obtained by conventional liposome preparation methods, its use as functional drug carriers for solving low efficacy of present liposomal drugs would have promising application potential.