Study On Redox Sensitivity Nano-drug Delivery System Based On Poloxamer 188

BackgroundCancer is a disease caused by a series of abnormal reactions,which leads to the disorder of normal physiological functions.Cancer cells have uncontrollable growth trends in their growth period,which causes great harm to the tissues and systems of patients.So far,there is no cure for cancer completely.In recent years,nanotechnology has been widely developed,which provides a good solution to improve the anti-tumor effects of drugs.PurposeThe purpose of this study is to develop a redox sensitive drug delivery system to targeted deliver doxorubicin（DOX）into cancer cells.Such systems are expected to improve the anti-tumor activity of free DOX and decrease its toxicity to normal tissues.Methods1.The poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX prodrugs were synthesized by ring-opening polymerization and amidation,respectively.The structures of the obtained prodrugs were studied by the nuclear magnetic resonance,infrared spectrophotometer and thermogravimetric analyzer,respectivley.2.The poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX nanoparticles（NPs）were fabricated with the solvent evaporation method.The size distribution,morphology,and zeta potential of obtained NPs were measured.Furthermore,their GSH responsiveness and drug release profiles were also studied.3.In vitro uptake and anti-tumor activity of the poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX NPs were studied using U87,4T1 and HCT116 cells as models,respectively.Balb/c mice were used as tumor bearing models to study the antitumor effects and biosafety of the poloxamer188-b-PCL-S-S-DOX NPs in vivo.Results1.The poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX polymer prodrugs were successfully prepared.2.The particle size of poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX nanoparticles dispersions are 117±0.8 nm and 125±0.03 nm,respectively.The potential values were-1.77±0.21 m V and-2.96±0.57 m V,respectively.The morphology of the two nanoparticles were spherical or nearly spherical,and they had good GSH responsiveness.3.Cell uptake tests showed that the poloxamer188-S-S-DOX and poloxamer188-bPCL-S-S-DOX NPs could be effectively taken in by U87 cells,4T1 cells and HCT116 cells,respectively.Cell tests suggested that the poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX NPs displayed higher in vitro anti-tumor effects than that of free DOX.In vivo safety experiments found that the poloxamer188-b-PCL-S-S-DOX and poloxamer188-S-S-DOX NPs did not induce damage on the blood and organs of treated mice.There was no significant difference in blood routine and blood biochemical indexes between the control group and the control group（NS,P > 0.05）.These phenomena indicated that the poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX NPs had good biological security.In vivo antitumor experiments showed that compared with free DOX,poloxamer188-b-PCL-S-S-DOX nanoparticles showed higher in vivo antitumor activity and significantly reduced the toxicity of free DOX.ConclusionThe poloxamer188-S-S-DOX and poloxamer188-b-PCL-S-S-DOX were successfully constructed as redox sensitive polymer prodrug systems,which had strong GSH sensitivity,good blood compatibility,low toxicity,good anti-tumor effect and cell uptake efficiency in vitro.It provides a new research direction for intracellular targeted delivery of antitumor drugs.