Codelivery of a pi-pi Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multidrug Resistance and Tumor Metastasis

摘要

The multidrug resistance (MDR) of cancer cells is a major obstacle in cancer chemotherapy and very few strategies are available to overcome it. Here, a new strategy is developed to codeliver a pi-pi stacked dual anticancer drug combination with an actively targeted, pH-and reduction-sensitive polymer micellar platform for combating multidrug resistance and tumor metastasis. In contrast to other methods, two traditional chemotherapeutics, doxorubicin (DOX) and 10-hydroxycamptothecin with complex aromatic pi-pi conjugated structures, are integrated into one drug delivery system via a pi-pi stacking interaction, which enables the released drugs to evade the recognition of drug pumps due to a slight change in the drug's molecular structure. The micelles exhibit active targeting of DOX-resistant human breast cancer MCF-7 cells (MCF-7/ADR) and have the ability to control the release of the drug in response to the microenvironmental stimuli of tumor cells. As a result, the codelivery of the pi-pi stacked dual anticancer drug combination displays high therapeutic efficacy in the MCF-7/ADR tumor model and successfully prevents the lung metastasis of tumor cells. The mechanism underlying the reversal of MDR is investigated, and the results reveal that the synergistic effect of the pi-pi stacked dual drugs promotes mitochondria-dependent apoptosis.