Preparation And Experimental Study Of Multifunctional Nanomedicine In The Treatment Of Ovarian Cancer Based On The Ferroptosis-inducing Effect

The pathogenesis of ovarian cancer is concealed.Most patients with ovarian cancer are at advanced stage when diagnosed.Ovarian cancer has some features,such as tendency to recur,immunosuppression and abdominal metastasis.The prognosis of the patients at advanced stage is poor.Ferroptosis is a newly discovered pathway of programmed cell death.Inducing ferroptosis has become a promising research interest for cancer treatment.As an interdisciplinary between nanoscience and medicine,nanomedicine can achieve the goals of tumor targeting,multifunctional integration,and precise treatment,and it provides new ideas for tumor treatment.First part Ferroptosis-inducing nanoliposomes in ovarian cancer treatmentObjectiveTo synthesize ferroptosis-inducing multifunctional nanoliposomes with magnetothermal effect,killing ovarian cancer cells and enhancing anti-tumor immunityMethodsFerroferric oxide was enclosed by dipalmitoylphosphatidylcholine,forming the magnetothermal responsive temperature sensitive nanoliposomes.Glucose oxidase and manganese dioxide were carried on the surface of nanoliposomes to induce ferroptosis of cancer cells.Programmed death ligand 1 monoclonal antibody was carried to enhance anti-tumor immunity.Folic acid was modified on the surface to achieve tumor targeting.Transmission electron microscope and other methods were used to explore the features of nanoliposomes.Magnetothermal conversion ability of liposomes was tested in alternating magnetic field.Catalytic ability was detected by colorimetry.Cytotoxity was tested.Cell uptake was detected by iron staining.The state of ferroptosis was detected by DCFH-DA and BODIPY 581/591 C11 probe.Tumor bearing mouse model was built to test the treatment effect of nanoliposomes via intravenous inj ection.ResultsThe diameters of ferroptosis-inducing nanoliposomes were around 100nm.Nanoliposomes have good dispersion and magnetothermal conversion ability,and could reach to 50℃.Colorimetry showed good catalytic ability.Nanoliposomes have good cancer cell killing effects,and these effects are enhanced under the alternating magnetic field.Folic acid and programmed death ligand 1 monoclonal antibody could enhance cell uptake of nanoliposomes.Nanoliposomes could enhance reactive oxygen species and promote lipid peroxidation of cancer cells.Nanoliposomes could effectively inhibit tumor growth and promote the infiltration of CD8+T cells in tumor under excitation of alternating magnetic field in vivo.SummaryThe nanoliposomes have good ferroptosis inducing ability,and have the abilities of magnetic thermal conversion,tumor targeting and antitumor immunity promoting effect.Second part Ferroptosis-inducing nanomotors in the treatment of ovarian cancer peritoneum metastasisObjectiveTo synthesize ferroptosis-inducing multifunctional nanomotors,killing ovarian cancer cells and inhibiting peritoneum metastasisMethodsJanus spherical nanomotors were synthesized by manganese dioxide and silicon dioxide,and then polyethyleneglycol and RSL3 were attached on the surface of the nanomotoes.Through transmission electron microscope and other methods to explore the features of nanomotors.The movement track was observed,and the velocity,mean square displacement and diffusion coefficient were calculated.Cell uptake was also observed under the driven by hydrogen peroxide.The reactive oxygen species,glutathione and lipid peroxidation were measured.The migration and invasion ability were tested by Transwell model.The expression of CD44 and spheroid formation experiment were practiced to evaluate the stemness of cancer cells.Mice model with peritoneum metastasis of ovarian cancer was used to evaluate the anticancer effect.ResultsThe nanomotors gad a Janus spherical structure and the diameter of nanomotors was around 100 to 200nm.Nanomotors had good movement ability in hydrogen peroxide solution and the ability can increase the uptake of nanomotors by tumor cells.Colorimetry showed good catalytic ability.Nanomotors could enhance reactive oxygen species,decrease glutathione and promoted lipid peroxidation of cancer cells.Nanomotors could inhibit the migration and invasion of tumor cells.Nanomotors could impair the expression of CD44 and spheroid forming ability.The anticancer effect was observed in vivo.SummaryThe nanomotors have good movement and ferroptosis inducing ability,and can reduce the stemness of cancer cells,and inhibit peritoneum metastasis of ovarian cancer.Conclusions1.The ferroptosis-inducing nanomedicines meets the needs for biological applications and has good biological effects;2.The ferroptosis-inducing nanomedicines can induce ferroptosis of ovarian cancer cells,and have the abilities of magnetothermal conversion,antitumor immunity promotion and stemness inhibition,and have good treatment effect for ovarian cancer.