Open AccessMultidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir
Author(s) -
Fan Li,
Zhang Silu,
Zhang Chunyuan,
Yin Chun,
Chu Zhiqin,
Song Chaojun,
Lin Ge,
Li Quan
Publication year - 2018
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201700289
Subject(s) - drug , cytosol , multiple drug resistance , endocytosis , chemistry , drug resistance , pharmacology , in vivo , intracellular , efflux , biophysics , cancer cell , drug delivery , drug carrier , cell , biochemistry , biology , cancer , antibiotics , microbiology and biotechnology , enzyme , genetics , organic chemistry
It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from the carrier into the cytosol and the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drug can be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drug from the NP carrier provides a feasible scheme for sustained drug release in cells, resulting in relatively stable cytosolic drug concentration level, particularly in the drug resistant case. By implementing an “optical switch” with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drug release is further promoted, which increases cytosolic drug concentration with good concentration retention. Enhanced drug efficacy in drug sensitive 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.