Preparation Of Stimulus-Responsive Nanoparticles And Their Anti-Cancer Effects By Free Radical Oxidation

Cancer is one of the major diseases that endanger human health.Traditional surgical treatment,radiation therapy,and chemotherapy are the main clinical treatments,but they still face some challenges,such as poor therapeutic effects and severe side effects on normal tissues.Recently,oxidative free radical-mediated cancer treatments have attracted increasing attentions from researchers.As cancer cells are more sensitive to free radicals than normal cells,thus oxidant free radicals could effectively kill cancer cells and hopefully reduce the side effects on normal cells.Currently,photodynamic therapy is one of the most typical free radicalmediated therapy,in which an external light source is applied to excite the photosensitizers and oxygen in cells to generate oxygen-containing free radicals for killing cancer cells.Although photodynamic therapy shows great potentials in clinical cancer treatments,it still has some deficiencies: i)the penetration depths of the exciting lights are very limited and thereby it cannot act on the deep-seated tumors in vivo;ii)the production of oxygen free radicals is heavily dependent on oxygen,and the hypoxic environment of the tumor limits the production of oxygen free radicals;iii)the high concentrations of reducing agent glutathione(GSH)in tumor will consume the generated free radicals;iv)the selectivity and targeting of free radical-medicated anticancer treatments need to be further improved.All these issues have limited the therapeutic potentials and development of free radicalmediated cancer treatments.To address the challenges mentioned above and improve the therapeutic effects of free radical-mediated cancer treatment,research in the following four aspects of were conducted in this thesis:First,aiming at the problem of limited penetration depth,this study constructed a hydroxyl radical-mediated photodynamic therapy platform based on upconversion/mesoporous silica nanoparticles with high-penetration-depth near infrared(NIR)light used as the stimulus source.The upconversion/mesoporous silica nanoparticles were synthesized,and loaded with rapaquinone in the pore channels,and then modified with light-sensitive monomethyl ester on their surface as nanovalves.Upon NIR light irradiation,upconversion/mesoporous silica nanoparticles were able to rapidly release the rapaquone from the nanopores,and the release amount was around 35 wt%,which was nearly 11 times that of the control.Released rapaquone was then catalyzed into hydrogen peroxide(H2O2)by the endoquinone oxidoreductase I in cancer cells.Subsequently,H2O2 was catalyzed into highly oxidant hydroxyl radical by upconverted lights.In vitro cell killing studies showed that the cell killing rate of upconversion/mesoporous silica nanoparticles under NIR light irradiation was around 73%,which was nearly 2.3 times that of control group without NIR irradiation.Secondly,to tackle the problem of the tumor hypoxia environment and high GSH concentration,oxygen-independent alkyl radical-mediated therapy with the inhibition GSH synthesis was constructed through the preparation of mesoporous carbon nanoparticles with azodiisobutyimidazoline hydrochloride(AIBI,initiator)and raloxifene(GSH inhibitor)loaded inside.Upon NIR light irradiation,photothermal effects of mesoporous carbon nanoparticles induced the decomposition of AIBI to oxygen-independent alkyl radical for killing cancer cell.At the same time,the released raloxifene inhibited the synthesis of antioxidant GSH further enhanced the anticancer efficacy.In vitro drug release experiments showed that both AIBI and raloxifene can be effectively release under 2.0 W/cm2 of 808 nm NIR light for 20 min,with release amounts of 22.1 and 34.7% respectively,which was about 7 times that of the control group without light irradiation.In vitro cancer cell killing results showed that the composite nanoparticles can effectively kill cancer cells under normal oxygen or tumor hypoxia conditions,and GSH inhibitors could significantly enhance the cell-killing abilities.In vivo results in nude mice showed that the tumor almost disappeared after treated with the composite material and did not recur within 14 days.Then,as for the low selectivity and targeting ability of traditional free radicalmediated cancer treatments,this study constructed a targeting-guided selective anticancer therapy by preparing cancer cell membrane coated cerium oxide nanoparticles.On the one hand,the homogeneous targeting of cancer cell membranes enabled the accumulation of nanoparticles at tumor site.On the other hand,cerium oxide nanoparticles selectively catalyzed H2O2 into oxidative hydroxyl radicals under tumor acid conditions,while no hydroxyl radicals were generated in normal tissues under neutral p H condition.In vitro cancer cell killing experiments showed that the killing abilities of nanoparticles gradually increased with the decreasing p H value,and the cell death rate under the tumor acidic condition was about 4.5 times that under normal tissue.In vivo imaging results demonstrated that homogeneous targeting ability of cancer cell membranes can indeed facilitate the enrichment of the nanoparticles at tumor sites.Additionally,after a single treatment,the tumor growth in nude mice can be effectively inhibited with no obvious damage on normal tissues and organs as well.Finally,based on the above studies,a triple-modal anti-cancer therapy was constructed with the characteristics of tumor-selectivity and no need for external light excitation.A cascade reaction enabled chemotherapy/starvation therapy /chemodynamic therapy anticancer nanoplatform was prepared based on enzymemodified metal-organic framework.The cell killing rate of triple-modal treatment was 1.4 times and 4.3 times that of dual-modal and single-modal treatment,respectively.Notably,this triple-modal therapy exhibited an excellent killing effect against a variety of cancer cells(liver cancer,glioma cells etc.).In vivo antitumor studies showed that after a single treatment,the tumor volume was significantly reduced and the tumor suppression rate was calculated to be 86.6%.The staining analysis of tissue sections showed that the composite had no obvious toxic and side effects on the organs of nude mice.This thesis constructed novel free radical-mediated cancer treatments based on stimulus-response nanomaterials for tackling the problems of insufficient depth of treatment,oxygen dependence,and low-selectivity existing in current treatments,and realized from single treatment to triple-modal syngerstic therapy.The work would shed lights on the design and construction of novel anti-tumor platforms.