Construction Of Oxidase-loaded Semiconductor Polymer Nanoplatform And Its Application In Combination Therapy For Tumors

Cancer,a disease with high mortality rate,has become a serious threat to human health.Therefore,the treatment of cancer has always been a hot topic in scientific research.Surgical treatment,radiotherapy and chemotherapy are three traditional cancer treatments that can inhibit tumor growth to some extent,but they have different defects.For example,surgical treatment may not completely remove the tumor and may cause recurrence.Chemotherapy has greater damage to the body due to poor specificity.And radiotherapy is limited by small irradiation range,different tumors and inconsistent sensitivity of tissues and organs,which affects the therapeutic effect.Based on this,various new treatments have been gradually discovered and developed.Semiconductor polymer nanoparticles have received extensive attention in the field of biomaterials due to their good biocompatibility.Semiconductor polymer nanoparticles are often used as photosensitizers or sonosensitizers because they can effectively produce reactive oxygen species or heat under ultrasound or laser,which can kill tumors.On the other hand,oxidases（such as glucose oxidase,lactate oxidase,etc.）are often used in the treatment of tumors because they can oxidize and decompose related substrates to produce H₂O₂.In this study,we synthesized two kinds of nanoplatforms loaded with oxidase and semiconductor polymers,and evaluated their various properties,including particle size,surface potential,reactive oxygen species production efficiency,cell compatibility,cell killing effect,etc.,and evaluated the therapeutic effect in vivo by using a mouse tumor model.In the second chapter,we constructed a hypoxic prodrug terazamine（TPZ）and glucose oxidase（GOx）-loaded alginate（ALG）hydrogel for photodynamic combined chemotherapy of melanoma.In vitro verification experiments showed that the hydrogel could be formed at tissue Ca²⁺concentration and could effectively produce singlet oxygen（¹O₂）.In vitro cell experiments showed that this hydrogel had almost no cytotoxicity without laser irradiation,but could effectively kill B16cancer cells after laser irradiation and produce a certain amount of reactive oxygen species in cells.In vivo experiments,it was evaluated by using a melanoma model.The results showed that after laser irradiation,the hydrogel could inhibit tumor growth under the action of photodynamic therapy（PDT）mediated by photosensitizer（PCPDTBT）,and combined with the catalytic reaction of glucose oxidase（GOx）.Both processes consumed oxygen in the tumor microenvironment,which in turn activated the Tirapazamine-mediated chemotherapy.The combination of the two can significantly inhibit tumor growth.In the third chapter,we constructed a dual-program activated semiconductor polymer nanocomposite for sonodynamic and chemodynamic combined immunotherapy of pancreatic cancer.¹H NMR spectroscopy demonstrates the successful synthesis of DSPE-PEG-TK and DSPE-PEG-PYR.UV,fluorescence,transmission electron microscopy（TEM）tests and release experiments showed that the nanoplatform was successfully synthesized,and the coupled lactate oxidase（LOX）could be released by ultrasound.In vitro cell experiments showed that under the action of ultrasound and H₂O₂,the nanocomposite had a significant killing effect on Panc02 cells and could induce tumor cell immunogenic cell death（ICD）.In vivo experiments,it was evaluated by using the Panc02pancreatic cancer model.The results showed that the dual-program activated nanoplatform had a good anti-tumor effect through the combined effect of sonodynamic therapy（SDT）and chemodynamic therapy（CDT）,and mediated ICD through SDT and CDT,activated DC and T cells to strengthen the body’s immunity against tumors.In summary,we constructed two oxidase-loaded semiconductor polymer nanoplatforms that can activate PDT or SDT under laser or ultrasound irradiation,and the loading of oxidase can promote the effect of chemotherapy or CDT and effectively inhibit tumor growth.Therefore,these two nanoplatforms provide promising solutions for the treatment of tumors.