Abstract
Multi-drug resistance (MDR) remains a major obstacle in cancer treatment while being heavily dependent on mitochondrial activity and drug efflux. We previously demonstrated that cationic lipids, such as the vitamin E succinate modified octahistidine-octaarginine (VES-H8R8) conjugate, target mitochondria, resulting in depolarized mitochondria and inhibited drug efflux in MDR breast cancer cells. We hypothesized that the effective cell uptake, efflux inhibition, and mitochondrial depolarization properties of VES-H8R8 would synergistically enhance the toxicity of a pH-sensitive prodrug of doxorubicin (pDox) when co-encapsulated in nanoparticles (NPs). pDox was successfully synthesized and validated for pH-sensitive release from NPs under lysosome-mimicking, acidic conditions. The synergistic effect of VES-H8R8 and pDox was confirmed against MDR breast cancer cells in vitro. Importantly, synergism was only observed when VES-H8R8 and pDox were co-encapsulated in a single nanoparticulate system. The synergistic mechanism was investigated, confirming superior pDox uptake and retention, Pgp efflux inhibition, mitochondrial depolarization, and enhanced induction of ROS, and apoptosis. This work demonstrates the translational potential of doubly-loaded NPs co-encapsulating pDox with VES-H8R8 to synergistically kill MDR breast cancer cells.
Highlights
Multi-drug resistance (MDR) remains a major obstacle in cancer treatment whereby MDR cancer cells are able to survive and proliferate under clinical doses of chemotherapeutic agents[1]
While all the values are in the range of neutral zeta potential (−20 to +20 mV), the trends from negative to positive charge is indicative of successful encapsulation of cationic VESH8R8 and palmityl-modified doxorubicin (pDox)[30,31]
The more neutral zeta potential of DNPs is attributed to the protonated amine of pDox neutralizing the free acids of P(LA-co-TMCC)-g-PEG, while the more positive zeta potential of VDNPs is attributed to positive charges found within both pDox and VES-H8R8
Summary
Multi-drug resistance (MDR) remains a major obstacle in cancer treatment whereby MDR cancer cells are able to survive and proliferate under clinical doses of chemotherapeutic agents[1]. Drug efflux is an active process, requiring adenosine triphosphate (ATP) for pumping various chemotherapeutics out of the cell, lowering the effective intracellular drug concentration[8] Both intrinsic and acquired MDR are heavily dependent on the mitochondria, making the mitochondria of MDR cancer cells an attractive intracellular target. VES-H8R8 demonstrated good cell uptake, retention and Pgp efflux inhibition in MDR cancer cells, which makes VES-H8R8 an ideal candidate for co-delivery with other chemotherapeutics, such as doxorubicin, for potential synergism. The co-encapsulation of doxorubicin and mitomycin C in NPs was therapeutically superior to free drug combination in vivo, with prolonged systemic circulation, enhanced tumor accumulation, and maintenance of synergistic drug ratios over 24 h19. This work demonstrates the synergistic mechanism of co-encapsulating a novel mitochondrial depolarizer and Pgp efflux inhibitor, VES-H8R8, with a pH-sensitive prodrug of doxorubicin in NPs against MDR cancer cells
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