Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir

Abstract

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.

Undifferentiated destruction of mitochondria by photoacoustic shockwave to overcome chemoresistance and radiation resistance in cancer therapy

“…To establish and identify the radiation/chemo-resistant tumor cells Chemoresistant HeLa/ADR (Adriamycin) and A549/DDP (Cisplatin) cells were obtained from Biotechnology.Co., Ltd and cultured according to the established protocol. 26,27,30,31 The results were expressed as IC 50 values calculated from the dose-survival curves of the established chemoresistant cells and the corresponding parental strains were verified and found to be significantly different (P < 0.05) (Fig. 2a-d).…”

The Establishment and Application Studies on Precise Lysosome pH Indicator Based on Self-Decomposable Nanoparticles

“…The 10 series self-decomposable nanoparticles were synthesized by the methodologies we reported before [ 13 – 16 ], with modified parameters. In a typical procedure, a certain amount of MB was firstly added to a mixture of ethanol (75 mL) with ammonia–water solution (25%, 3.4 mL), after that certain amount of TEOS was added.…”

Precise lysosome pH indicator based on self-decomposable nanoparticles

“…The 10 series self-decomposable nanoparticles were synthesized by the methodologies we reported before [18][19][20][21], with modified parameters. In a typical procedure, certain amount of MB was firstly added to a mixture of ethanol (75 mL) with ammonia-water solution (25%, 3.4 mL), after that certain amount of TEOS was added.…”