ROS and GSH-responsive S-nitrosoglutathione functionalized polymeric nanoparticles to overcome multidrug resistance in cancer.
Multidrug resistance of cancer cells is one of the major obstacle for chemotherapeutic efficiency. Nitric oxide (NO) has raised the potential to overcome multidrug resistance (MDR) with low side effects. Herein, we report a reactive oxygen species (ROS) and glutathione (GSH) responsive nanoparticle for the delivery of NO prodrug such as S-nitrosoglutathione (GSNO), which was chemically conjugated to an amphiphilic block copolymer. The GSNO functionalized nanoparticles show high NO loading capacity, good stability and sustained NO release with specific GSH activated NO-releasing kinetics. Such GSNO functionalized nanoparticles delivered doxorubicin (DOX) in a ROS triggered manner and increased the intracellular accumulation of DOX. However, in normal healthy cells, showing physiological concentrations of ROS, these nanoparticles presented good biocompatibility. The present work indicated that these multifunctional nanoparticles can serve as effective co-delivery platforms of NO and DOX to selectively kill chemo-resistant cancer cells through increasing chemo-sensitivity. STATEMENT OF SIGNIFICANCE: In this work, we constructed nitric oxide donor (S-nitrosoglutathione, GSNO) functionalized amphiphilic copolymer (PEG-PPS-GSNO) to deliver doxorubicin (DOX). The developed PEG-PPS-GSNO@DOX nanoparticles presented high NO capacity, ROS triggered DOX release and GSH triggered NO release. Thus NO reversed the chemo-resistance in HepG2/ADR cells increasing intrcellular accumulation of DOX. Furthermore, these PEG-PPS-GSNO@DOX nanoparticles exhibited biocompatibility to healthy cells and toxicity to cancer cells, due to elevated ROS.
['Wu|Wen|W|', 'Chen|Min|M|', 'Luo|Tingrong|T|', 'Fan|Ying|Y|', 'Zhang|Jinqiang|J|', 'Zhang|Yan|Y|', 'Zhang|Qianyu|Q|', 'Sapin-Minet|Anne|A|', 'Gaucher|Caroline|C|', 'Xia|Xuefeng|X|']
D016923:Cell Death D004317:Doxorubicin D065546:Drug Liberation D018432:Drug Resistance, Multiple D019008:Drug Resistance, Neoplasm D004705:Endocytosis D057809:HEK293 Cells D056945:Hep G2 Cells D006801:Humans D020128:Inhibitory Concentration 50 D053758:Nanoparticles D009369:Neoplasms D009569:Nitric Oxide D010316:Particle Size D011092:Polyethylene Glycols D011108:Polymers D066244:Proton Magnetic Resonance Spectroscopy D017382:Reactive Oxygen Species D026422:S-Nitrosoglutathione D013440:Sulfides
S-nitrosoglutathione Multidrug resistance of cancer Nitric oxide Glutathione-responsive Reactive oxygen species-responsive