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.

A three-step approach was used to enhance anticancer activity via targeted delivery, intracellular drug burst release, and depressed drug efflux.

Paclitaxel (PTX) is one of the most effective antineoplastic drugs. Its current clinical administration Taxol ® is formulated in Cremophor EL, which causes serious side effects. Nanoparticles (NP) with lower systemic toxicity and enhanced therapeutic efficiency may be an alternative formulation of the Cremophor EL-based vehicle for PTX delivery. In this study, novel amphipathic 4-arm-PEG-TPGS derivatives, the conjugation of D-α-tocopherol polyethylene glycol succinate (TPGS) and 4-arm-polyethylene glycol (4-arm-PEG) with different molecular weights, have been successfully synthesized and used as carriers for the delivery of PTX. These 4-arm-PEG-TPGS derivatives were able to self-assemble to form uniform NP with PTX encapsulation. Among them, 4-arm-PEG 5K -TPGS NP exhibited the smallest particle size, highest drug-loading efficiency, negligible hemolysis rate, and high physiologic stability. Therefore, it was chosen for further in vitro and in vivo investigations. Facilitated by the effective uptake of the NP, the PTX-loaded 4-arm-PEG 5K -TPGS NP showed greater cytotoxicity compared with free PTX against human ovarian cancer (A2780), non-small cell lung cancer (A549), and breast adenocarcinoma cancer (MCF-7) cells, as well as a higher apoptotic rate and a more significant cell cycle arrest effect at the G2/M phase in A2780 cells. More importantly, PTX-loaded 4-arm-PEG 5K -TPGS NP resulted in a significantly improved tumor growth inhibitory effect in comparison to Taxol ® in S180 sarcoma-bearing mice models. This study suggested that 4-arm-PEG 5K -TPGS NP may have the potential as an anticancer drug delivery system.