Design,Synthesis And Antitumor Studies Of Hydrogen Peroxide-Based Functional Nanomaterials

The development of nanotechnology provides new opportunities for the treatment of malignant tumors.Nanomaterials,with their large specific surface area,versatile physical and chemical properties,convenient surface modification process,have natural advantages in the anticancer drugs loading and the design of nano-precursors.They not only have better biocompatibility,but also can significantly reduce the side effects of chemotherapy drugs.H2O2,as a potent and side-effect-free chemotherapeutic agent,has great potential in the field of tumor therapy.However,the relatively poor chemical stability of H2O2 has long been restricting its development and application.Using nanotechnology to transform it into more stable nanoparticles while retaining the active eomponent of H2O2,and achieving the controllable release of H2O2 at specific sites,this strategy will usher in new vitality for the development and clinical transformation of H2O2 molecules in the field of tumor treatment.In this paper,we have designed and optimized a few functional nanomaterials based on H2O2,and systematically studied their anti-tumor performance,aiming at improving the efficiency of tumor treatment.The main research contents are as follows:(1)in situ H2O2 nanogenerator for responsive tumor therapy.Through experimental exploration and performance evaluation,the layered double hydroxide(LDH)is selected as a nano-carrier capable of supporting H2O2 stably.This kind of nano-carrier can realize the load of H2O2 through strong chemical coordination rather than physical electrostatic adsorption,thus can greatly improve the chemical stability of H2O2.And under acidic conditions(such as tumor regions),H2O2 molecules can be released again through proton ligand exchange.The extra cellular H2O2 content will then induce cell oxidative stress which can further interfere with redox signal and increase intracellular oxidation levels,resulting in lipid peroxidation and cell proliferation inhibition.This nano-carrier has considerable in vivo anti-tumor effect.(2)Calcium overload-mediated tumor therapy by calcium peroxide nanoparticles.In order to further control the size of the nano-system and improve the chemical stability of H2O2,the active components of H2O2 are tried to crystallized as nano-precursor drugs by chemical reaction.After the systematic exploration of preparation methods,single phase CaO2 nanocrystals with adjustable size are obtained by wet chemical method at room temperature.The nanoparticles are crystallized by the reaction of H2O2 molecule and calcium ion under certain conditions,and cannot be dissolved in aqueous solution and shows chemical inertia.But they can be gradually resolved into Ca2+ and H2O2 in the acidic conditions,thus can realize the H2O2 quick release responding to the tumor acidic environment.Then,the biological effects of free Ca2+ in tumor cells and its synergistic anti-tumor mechanism with H2O2 have also been fully studied.Cellular oxidative stress induced by H2O2 can interfere with calcium-related ion channels,as a result,the decomposed Ca2+ unable to be stored or discharged out of the cell timely,resulting in the abnormal retention of excessive Ca2+ in the cytoplasm,and leading to calcium overload.The calcium overload ean turn regulatory ealcium signals into apoptotic signals,leading to cell death.In addition,the abnormal accumulation of Ca2+ can promote the development of tumor calcification,which will be further conducive to the inhibition of tumor proliferation and CT image monitoring.This strategy applies calcium overload phenomenon into tumor therapy,and we named it as calcicoptosis.Also,this work demonstrates that the biological effects of some metal ions can also contributive to tumor therapy,which opens a new window for the development of anti-tumor nanodrugs.(3)Radiation-assisted metal ion interference tumor therapy by barium peroxide-based nanoparticles.Under the dual guidance of the above-mentioned synthesis process of peroxide nanosystem and the biological effect of metal ions,BaO2 nanomaterials containing heavy metal element are prepared to improve the sensitization effect of tumor radiotherapy.At the same time,through surface modification of GLDA metal chelating agent,biological function transformation of barium ions can be realized.BaO2 nanomaterials are chemically inactive in aqueous solution,but under X-ray irradiation,H2O2 can be transformed into highly active hydroxyl radicals,while barium ions as a high-Z element can get higher X-ray deposition.Therefore,the nanocrystals with the combination of the two can achieve a high yield of hydroxyl radical,improving the radiation sensitization.Besides,the generated highly active hydroxyl radical can also destroy the molecular structure of GLDA at the same time,making it lose the ability to bind metal ions and causing the leakage of free Ba2+.Ba2+ as a highly effective potassium channel blocker can further exert its biological effects to synergistically inhibit tumor proliferation and growth.This strategy,which we named as ion-interference therapy,applies functional metal ions into tumor therapy,using the biological effects of metal ions to interfere with normal proliferation and the growth of tumor cells,and finally achieve the cooperative effect of tumors treatment.This new antitumor strategy will provide the enlightening idea for other functional ions to be used in the coordinated treatment of tumors,and open a new way for the research and development of antitumor nanodrugs.