Enhanced in vitro antitumor efficacy of a polyunsaturated fatty acid-conjugated pH-responsive self-assembled ion-pairing liposome-encapsulated prodrug

The development of clinical chemotherapeutics is always challenging due to the toxicity and side effects of drugs not only for tumor cells but also for normal cells. Therefore, nano-drug delivery systems and prodrug strategies have been applied to address this challenge. Herein, we report a liposome-encapsulated small-molecule prodrug nanosystem, self-assembled by doxorubicin (DOX) and mixed polyunsaturated fatty acid (MPUFA) ion-pairing (MPUFAs-DOX@Liposomes), which has a high omega-3 PUFA content. The increased lipophilicity of ion-paired MPUFAs-DOX can significantly improve the drug loading efficiency (∼97%). Electrostatic interaction, the hydrophobic effect and hydrogen bonding between the ion-pairing agents led to superior pH-responsive release of DOX from liposomes over DOX-loaded liposomes (DOX@Liposomes), with a more rapid release rate at pH 5.0 than at pH 7.4, which is beneficial for decreasing the toxicity of DOX under physiological conditions. Finally, the in vitro antitumor effects were investigated for two tumor cell types, A549 and MCF-7, and the results demonstrated that MPUFAs-DOX@Liposomes showed the highest cytotoxicity compared with free DOX and DOX@Liposomes because of the ready uptake under the effect of PUFAs. Hence, liposomes loaded with ion-paired MPUFAs-DOX is a promising formulation for combination cancer therapy.