Redox Dyshomeostasis Strategy For Efficient Hypoxic Tumor Therapy

Redox homeostasis refers to the dynamic balance between intracellular oxidized and reduced states,which plays an important role in maintaining the normal physiological processes of cells.However,redox homeostasis,as an innate cellular defense mechanism,seriously restricts the reactive species-mediated tumor therapy,such as reactive oxygen species(ROS)or reactive nitrogen species(RNS).Especially for hypoxic tumors,activated antioxidant systems strengthen the antioxidant defense ability of hypoxic tumor cells,which seriously restricts reactive species-mediated various tumor treatments.Consequently,intracellular redox homeostasis may be a new target for tumor therapy.Of note,regulating redox homeostasis by nanomaterials is expected to achieve efficient hypoxic tumor therapy with the development of nano-biomedicine.In this study,according to the biological characteristics of redox homeostasis and hypoxia tumor,two kinds of functional nanomaterials based on zeolitic imidazolate frameworks were designed and synthesized,which initially realized the efficient treatment of hypoxic tumor,and further explored the corresponding cellular biological mechanism.The main research contents are as follows:1.DNAzyme-loaded electrophilic zeolitic imidazolate frameworks for ROS-mediated efficient hypoxic tumor therapy:The enhanced antioxidant defense ability of hypoxic tumors can effectively lower ROS levels,which makes hypoxic tumors insensitive to various ROS-mediated tumor treatments.In order to solve the bottleneck problem,we proposed a redox dyshomeostasis(RDH)strategy based on FeCysPW@ZIF-82@CATDz nanoplatform to disrupt redox homeostasis,and its application to improve chemodynamic therapy(CDT)-mediated hypoxic tumor therapy.Once endocytosed by tumor cells,the catalase DNAzyme(CAT Dz)loaded zeolitic imidazole framework-82(ZIF-82@CAT Dz)shell can be degraded into Zn²⁺as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione(GSH)depletion under hypoxia,both of which lead to intracellular RDH and H₂O₂ accumulation.These cells show an increase in sensitivity to ROS and are effectively killed by ferrous cysteine-phosphotungstate(Fe Cys PW)induced CDT.In vitro and in vivo data demonstrate that the p H/hypoxia/H₂O₂ triple stimuli responsive nanocomposite can significantly reduce ROS tolerance in hypoxic tumors and efficiently kill hypoxic tumors.Overall,the RDH strategy provides a new way of thinking and universal treatment for ROS-mediated hypoxic tumor therapy.2.Novel electrophilic zeolitic imidazolate frameworks for RNS-mediated efficient hypoxic prostate cancer therapy:Compared with ROS,RNS is another kind of intracellular active species,which can damage tumor cells by oxidizing biological macromolecules.But regrettably,due to redox homeostasis and some uncontrollable RNS donors,it is relatively difficult to specifically produce RNS in tumor sites,especially deep or hypoxic tumor sites.Based on this,we designed and constructed novel ZIF-82-PVP nanoparticles with good biocompatibility,and proposed a new strategy of X-ray-controlled release of RNS for hypoxic prostate cancer therapy.The acidic tumor microenvironment facilitated ZIF-82-PVP disintegration to release electrophilic ligands and Zn²⁺ions.Besides acting as a consumer of GSH under hypoxia,the 2-n Im ligand could produce nitrite(NO₂^-)upon X-ray stimulation.Notably,dissociated Zn²⁺specifically limits the migration and invasion of prostate cancer cells through ion interference.Both in vitro and in vivo experiments indicated that ZIF-82-PVP nanoparticles under X-ray irradiation not only can effectively induced the apoptosis of hypoxic prostate cancer cells,but also limited their metastasis.Overall,the strategy provides a new opportunity for RNS-mediated hypoxic tumor therapy and broadens the strategy of non-ROS-mediated tumor therapy.3.Cellular biological mechanism of RNS-mediated nitrosative stress for hypoxic prostate cancer therapy:As a kind of active species different from ROS,RNS has efficiency killing ability of hypoxic tumors,but its specific therapeutic mechanism is still unclear.Based on this,we preliminarily explored the cellular biological mechanism of ZIF-82-PVP for hypoxic prostate cancer therapy from the cellular structure and molecular level by means of bio-TEM,laser confocal microscopy and Western blot,and proposed a novel mechanism of nitrosative stress on tumor killing.Using ZIF-82-PVP for hypoxic prostate cancer therapy as an example,the results showed that X-ray triggered NO₂^-not only can damage cells by enhancing nitrosative stress but can also inhibit autophagy originating from ROS and tumor hypoxia.In addition,the released Zn²⁺can inhibit the metastasis of hypoxic prostate cancer by specifically inhibiting the expression of MMP-2 and MMP-9 in prostate cancer cells.These changes in cell biology,coupled with redox dyshomeostasis,enhance the therapeutic efficacy of hypoxic prostate cancer.The novel mechanism of nitrosative stress on tumor killing not only lays a solid theoretical foundation for RNS-mediated tumor therapy,but also provides a reference for new nitrosative stress-mediated tumor therapy.