ROS and GSH-responsive S-nitrosoglutathione functionalized polymeric nanoparticles to overcome multidrug resistance in cancer

• Published in: Acta biomaterialia Vol. 103; pp. 259 - 271
• Main Authors: Wu, Wen, Chen, Min, Luo, Tingrong, Fan, Ying, Zhang, Jinqiang, Zhang, Yan, Zhang, Qianyu, Sapin-Minet, Anne, Gaucher, Caroline, Xia, Xuefeng
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2020; Elsevier BV; Elsevier
• Subjects: Bile; Biochemistry; Biochemistry, Molecular Biology; Biocompatibility; Bioengineering; Biomaterials; Block copolymers; Cancer; Cell Behavior; Cell Death - drug effects; Cellular Biology; Doxorubicin; Doxorubicin - pharmacology; Drug Liberation; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Endocytosis - drug effects; Glutathione; Glutathione-responsive; HEK293 Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Life Sciences; Multidrug resistance; Multidrug resistance of cancer; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Neoplasms - drug therapy; Neoplasms - pathology; Nitric Oxide; Organic chemistry; Particle Size; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polymers - chemical synthesis; Polymers - chemistry; Proton Magnetic Resonance Spectroscopy; Reaction kinetics; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reactive oxygen species-responsive; S-nitrosoglutathione; S-Nitrosoglutathione - pharmacology; Side effects; Subcellular Processes; Sulfides - chemical synthesis; Sulfides - chemistry; Multidrug resistance of cancer; Reactive oxygen species-responsive; S-nitrosoglutathione; Nitric oxide; Glutathione-responsive
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2019.12.016

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. 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. [Display omitted]