Doxorubicin-Loaded All-Trans Retinoic Acid Dimer Phospholipid Liposomes as Co-Delivery System to Reverse Drug Resistance in Breast Cancer

Drug resistance is one of the major reasons for chemotherapy failure in breast cancer clinical therapy. In this study, a novel liposomal two-drug co-delivery delivery system was assembled from all-trans retinoic acid (ATRA) dimer phospholipid conjugate (diATRA-PC) and developed as a doxorubicin (DOX) carrier to overcome drug resistance in breast cancer. The DOX encapsulated diATRA-PC liposomes (diATRA-PC/DOX liposomes) were prepared by classic method, with a uniform size distribution between 50–100 nm. The free ATRA and DOX were released from liposomes simultaneously under simulated tumor intracellular environment. Moreover, the diATRA-PC liposomes exhibited enhanced cellular uptake, cytotoxicity and migration, inhibiting capacity against DOX-resistant human breast cancer cell line (MCF-7/ADR) when compared with controls. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the diATRA-PC/DOX liposomes had an effective promotion of apoptosis in DOX-resistant cells, with up-regulation of Caspase-3 and down-regulation of Bcl-2 mRNA expression. One could speculate that the reversed drug resistance in MCF-7/ADR cells was attributed to the enhanced cellular uptake of DOX by cancer cells in overcoming the drug efflux. In addition, pharmacokinetics studies showed that diATRAPC/DOX liposomes had a longer circulating time in comparison with free drug. In summary, the diATRA-PC liposomes can be regarded as a potential multi-drug combination therapeutic system for reversing drug resistance in breast cancer.