Studies On The Controlled Release Nanomaterials Of Nitric Oxide And Exploration Of The Biofunctions In Neoplasm Model

Nitric oxide has been proved to have multiple biofunction such as vasodilator,inhibitior of platelet aggregation,neurotransmitter for neural signaling,neural cell regulation,signal molecule in early embryonic development and embryo implantation,participating in immune response,and regulation of tumor occurrence,development and migration.In last 20 years,some reports demonstrated that NO plays roles in inhibition of tumor growth and migration.The involved process may include:mediating cytotoxicity of macrophages to tumor cells,inducing oncolytic effect of endothelial cell,reacting with superoxide radical to generate reactive nitrogen species which could destroy the DNA of tumor cells,affecting energy metabolism of tumor,activating the expression of p53 which leads to apoptosis of tumor cells,inhibiting tumor migration through inhibiting platelet aggregation,increasing sensitivity of tumor cells to chemotherapy drugs.Further studies pointed out that NO could reverse the MDR of tumor cells.NO as an antioxidant could decrease the oxidative stress in tumor and refrain from drug resistance adaption of cells.Moreover,NO can conjugate with the heme group of guanylate cyclase and maintain the ’oxy’ conformation to inhibit the activation of some transmembrane proteins.The NF-κB mediated apoptosis pathway and the antioxidant activity of GSH could also be inhibited by NO.There are several NO drugs have been developed and used in clinical treatment.In recent years,with the development of nanotechnology,the noval NO donors or carriers based on nanomaterials have also been developed constantly.To study and develop biocompatibility,stability,and controlled release nanomaterials of nitric oxide and explore their biofunctions in the field of biomedical applications,particularly the tumor therapy,is becoming a research hotspot.In this research,several NO nano-carrier donors,including GO-BNN6 which is a near-infrared light responsive NO donor based on two dimension graphene oxide,mPEG-PLGA-BNN6-DOX and mPEG-PEI-PLA-PTX-NO which are multifunctional and biocompatible nanomedicines were designed and synthesized.The NO and chemotherapeutics release of these nanocompounds could be triggered by light or spontaneously and lead to a synergy therapy and chemosensitization.To investigate the controlled release nanomaterials of nitric oxide and explore their biofunctions in neoplasm model,we have carried out following studies:1.A novel sandwich nanomedicine(GO-BNN6)for near-infrared(NIR)light responsive release of nitric oxide(NO)has been constructed by self-assembly of graphene oxide(GO)nanosheets and a NO donor BNN6 through the π-π stacking interaction.The GO-BNN6 nanomedicine has an extraordinarily high drug loading capacity(1.2 mg BNN6 per mg GO),good thermal stability,and high NIR responsiveness.The NO release from GO-BNN6 can be easily triggered and effectively controlled by adjusting the switching,irradiation time and power density of NIR laser.The intracellular NIR-responsive release of NO from the GO-BNN6 nanomedicine causes a remarkable anti-cancer effect.2.Multidrug resistance(MDR)is responsible for the relatively low effectiveness of chemotherapeutics.Herein,a nitric oxide(NO)gas-enhanced chemosensitization strategy is proposed to overcome MDR by constructing a biodegradable nanomedicine formula based on BNN6/DOX co-loaded mPEG-PLGA.On one hand,the nanomedicine is featured with high biocompatibility due to the high density of PEG and biodegradable PLGA.On the other hand,the nanoformula exhibits excellent stability under physiological conditions but stimuli-responsive decomposition of BNN6 for NO gas release upon ultraviolet-visible irradiation.More importantly,after triggering NO release,gas molecules would be generated to break the nanoparticle shell and lead to the release of doxorubicin.Furthermore,NO was demonstrated to reverse the MDR of tumor cells and enhance the chemosensitization for doxorubicin therapy.3.Nitric oxide as a hopeful chemosensitizer attracts more attention in anti-multidrug resistance tumor therapy.In this study,a three-segment amphiphilic copolymer was synthesized through click reaction by azido and alkyne group.The hydrophobic PLLA core encapsulated hydrophobic drug paclitaxel,the PEI part with abundant secondary amine was utilized to load nitric oxide gas molecule and produce ’proton sponge effect’ to assist the loaded drug escape into the cytoplasm to play a cytotoxic effect.The mPEG shell provided a hydrophilic interface and led the copolymer to self-assemble into micelles in water phase for biological application.This multifunctional mPEG-PEI-PLLA-PTX-NO has good biocompatibility and high penetration rate of cell membrane.The incorporated nanomedicine was able to release NO spontaneously under physiological conditions and enhanced the in vitro cytotoxicity for PTX and NO synergistic therapy,demonstrating potential application in the combination treatment of MDR cancer.