Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir

It is discovered that sustained cytosolic drugrelease at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drugefficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drugmovement between the drugreleased from the carrier into the cytosoland the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drugcan be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drugfrom the NP carrier provides a feasible scheme for sustained drugrelease in cells, resulting in relatively stable cytosolic drugconcentration level, particularly in the drugresistant case. By implementing an "optical switch" with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drugrelease is further promoted, which increases cytosolic drugconcentration with good concentration retention. Enhanced drugefficacy in drugsensitive as well as resistant models is demonstrated both in vitro and in vivo. Such a mechanism is shown to efficiently circumvent multidrug resistance, and at the same time largely reduce the systemic toxicity of the anticancer drug.