Combination delivery of Adjudin and Doxorubicin via integrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells

Combination therapy has been regarded as a potent strategy to overcome multidrug resistance (MDR). In this study, we adopt Adjudin (ADD), a mitochondria inhibitor, and Doxorubicin (DOX), a common chemo-drug, to treat drug-resistant cancer cells (MCF-7/ADR) in combination. Given the different physico-chemical properties of ADD and DOX, we develop a novel drug formulation (ADD-DOX (M)) by integrating drug conjugation and nanocarrier approaches to realize the co-delivery of the two drugs. We demonstrate the conjugation of ADD and DOX via formation of an acid-sensitive hydrazone bond, and then the encapsulation of ADD-DOX conjugates by DSPE-PEG2000 micelles with high drug encapsulation efficiency and well-controllable drug loading efficiency. The obtained ADD-DOX (M) micelles are found to be stable under physiological conditions, but can rapidly release drugs within acidic environments. Following cellular experiments confirm that ADD-DOX (M) vehicles can be internalized by MCF-7/ADR cancer cells through an endocytic pathway and exist within the moderate acidic endolysosomes, thus accelerating the hydrolysis of ADD-DOX and the release of free ADD and DOX. As a result, the ADD-DOX (M) formulation exhibits an excellent anti-MDR effect. In summary, we for the first time report the combinational use of ADD and DOX with an effective co-delivery strategy for the treatment of MDR cancer cells.