ROS And GSH-responsive Nitric Oxide Releasing Nanoparticles Reversing Multidrug Resistance In Tumor

The incidence and mortality of cancer is second only to cardiovascular disease.In 2015,there were 4.29 million new cases of cancer,accounting for 20% of new cases worldwide,as well as 2.81 million death,which seriously threatened health of humans.There are many cancer treatments,including surgery,chemotherapy,radiation therapy,and molecular targeted therapy,in which chemotherapy plays an important role.However,as the use of chemotherapeutic drugs increases during cancer treatments,multidrug resistance has gradually become a huge obstacle to cancer treatments.In the field of overcoming multidrug resistance,nitric oxide?NO?has become a biocompatible alternative compared to toxic chemotherapy sensitizers.However,the instablility and low bioavailability of NO limits its application in the field of tumor suppression.Nanocarriers can improve its stability and expand its application.Although a large number of nitric oxide donors and carriers have been developed to improve NO stability,a nanomaterial that can be safely used,stably stored,and controlled NO release is still need to be explored.Targeted delivery and controlled release of NO locoregionally are in high demand and challenging in cancer treatment.Herein,we designed and synthesized S-nitrosoglutathione functionalized methoxy poly?ethylene glycol?-poly?propylene sulfide??PEG-PPS-GSNO?.The amphiphilic copolymer was used to deliver doxorubicin hydrochloride?DOX.HCl?,the model drug.The physicochemical properties of developed PEG-PPS-GSNO were analyzed as well.The chemical structure of PEG-PPS-GSNO was identified by NMR and IR spectrophotometry.The molecular weight distribution of the material was characterized by gel permeation chromatography?GPC?.The nanoparticles loaded with DOX.HCl were prepared by emulsion-solvent evaporation method,resulting in stable and uniform nanoparticles monitored by nanoparticle size analyzer and transmission electron microscopy.Under PBS conditions,nanoparticles can release nitric oxide slowly and improve the stability of GSNO;under the stimulation of reactive oxygen species?ROS?,85.0±7.8%of DOX was released from the nanoparticles responsively;under the stimulation of reduced glutathione?GSH?,96.0±7.2%of NO was responsively released from the nanoparticles,proving the nanoparticles had good controlled release properties.Biocompatibility experiments showed that the material had no significant cytotoxicity.Incubated with the doxorubicin-resistant hepatoma cells?HepG2/ADR?,PEG-PPS-GSNO@DOX nanoparticles presented IC₅₀0 value 3 times less than free DOX.HCl,successfully reversing tumor multidrug resistance.In addition,we have verified that PEG-PPS-GSNO@DOX nanoparticles promoted the uptake of DOX by HepG2/ADR cells,as well as induced late apoptosis of tumor cells,to reverse the multidrug resistance.In the study,GSNO functionalized amphiphilic copolymer served as an efficient NO and chemotherapeutic drug delivery platform,holding great promise in cancer combinatorial treatment to overcome multidrug resistance.