Construction Of Mesoporous SiO₂ Coated Rare Earth-Based Nanosystems For Phototherapy Of Tumors

Phototherapy is an effective way to treat various diseases using specific wavelengths and intensities of light.However,its therapeutic effects are often impaired by the limited depth of light penetration in biological tissues.Current methods of optical transmission often require optical fiber or catheter insertion,which not only limits patient mobility,but also poses the problem of incompatibility with chronic implants.Compared to implantable optical fibers or catheters,nanomaterials can be easily injected into the body with minimal invasivity,and are surface functionalized to improve their biocompatibility and cell accumulation efficiency.Among them,rare-earth-based photoconversion nanomaterials,such as upconversion nanoparticles and X-ray fluorescence scintillators,can convert near-infrared light or X-ray into ultraviolet or visible light,suitable for active phototherapy.Based on this,the design of multifunctional nanocomposites for combined diagnosis and treatment systems including integrated phototherapy with near-infrared or X-ray light source as exogenous stimulation,and rare-earth based nanomaterials as optical transducers is of great significance for promoting tumor clinical treatment.The main contents are as follows:The surface of yttrium based rare earth up-conversion material was coated with mesoporous silicon by microemulsion method,and the photothermal agent polyoxometalate cluster and doxorubicin hydrochloride were supported on this material.At last,UCNPs@m Si O₂-POM-DOX@FC nanocomposites were encapsulated by folic acid coupled with chitosan molecules.As a gated valve,folate-coupled chitosan can not only protect the leakage of chemotherapy drugs and achieve sustained release chemotherapy,but also specifically target tumor cells.Due to the acidity and reducibility of the tumor microenvironment,the absorption of polyoxometalate clusters in the near-infrared region is significantly improved,thus achieving efficient photothermal therapy.In vivo experiments showed that phototherapy combined with chemotherapy could effectively inhibit tumor growth,with a tumor inhibition rate of 71.8%,which was significantly better than chemotherapy or photothermal therapy alone.Gadolinium was replaced by yttrium in up-conversion nanoparticles,and photosensitizer chlorin e6（Ce6）was introduced while mesoporous silicon was coated.Then calcium phosphate was grown in situ to obtain UCNPs@Ce6@m Si O₂@Ca P nanocomposites.The negative calcium phosphate shell not only increased the loading rate of doxorubicin hydrochloride（91.8%）,but also achieved p H response sustained release chemotherapy.Under near-infrared light irradiation,upconversion nanoparticles convert near-infrared photons into visible light to activate Ce6 for photodynamic therapy.This kind of chemotherapy combined with photodynamic therapy avoids the disadvantage that photothermal therapy may cause thermal damage to the surrounding tissue,and the therapeutic effect is significantly better than the above chemotherapy combined with photothermal therapy,and the tumor inhibition rate is 86.9%.Given the problems of the small pore size of mesoporous silicon and the inherent hypoxic and antioxidant environment of the tumor,the effect of photodynamic therapy was impaired.A dual-continuous phase microemulsion method was used to coat the surface of rare earth conversion nanoparticles with large pore size mesoporous silicon,and the nanoparticles weregraftedwithS-nitrosomercaptan（RSNO）.Then,UCNPs@DMSN-SNO@Cu O₂-Ce6-PEG nanocomposites were obtained by loading Ce6 and copper peroxide nanodots.In the acidic tumor microenvironment,the nanocomplex releases Cu²⁺and hydrogen peroxide and initiates a series of cascades,resulting in efficient chemokinetic treatment and nitric oxide（NO）release through Fenton-like reactions and Cu²⁺mediated RSNO decomposition.At the same time,the consumption of glutathione and relieve tumor oxygen deficiency.Importantly,reactive oxygen species and NO spontaneously generated active nitrogen,which directly induced DNA damage by triggering free radical peroxidation,improved the anti-cancer efficacy,and the tumor inhibition rate in vivo was88.4%.To solve the problems of limited near-infrared light penetration,poor stability of organic photosensitizers,and easy photobleaching in the previous three studies,we introduced X-ray and inorganic photosensitizers to achieve radiotherapy sensitization of rare-earth-based nanocomposites.First of all,using the improved phase bicontinuous microemulsion method in lutetium rare earth fluorescent scintillator（SCNPs）surface coated aperture adjustable mesoporous silica,and a variety of Ce O_x template in situ growth,to get different structure SCNPs@DMSN@Ce O_x-PEG nanocomposites.By regulating and optimizing the size of Ce O_x,its maximum UV–vis absorption peak can fluctuate within 300～354 nm,to perfectly match the X-ray excitation emission of SCNPs and achieve better energy transfer.In addition,Ce⁴⁺-dominated Ce O_x can consume glutathione,relieve tumor hypoxia through catalase activity,and enhance the anti-tumor effect,the tumor inhibition rate in vivo was 82.9%.Due to the problems of low yield of active nitrogen and easy repair of DNA damage during radiotherapy,RSNO was grafted on lutetium based SCNPs coated with mesoporous silicon of three pore sizes and then loaded with g-C₃N₄ quantum dots to obtain PEG/SCNPs@DMSN-SNO-g-C₃N₄ nanocomposites.SCNPs can convert X-ray photons to ultraviolet light,which activates RSNO and g-C₃N₄ to synchronously release NO and superoxide anions,and spontaneously cooperate to form reactive nitrogen.The yield of reactive nitrogen can be significantly improved by optimizing the pore size of mesoporous silicon.When the pore size of mesoporous silicon is about 10.93 nm,the yield of reactive nitrogen is the highest.High concentration of active nitrogen not only overcame radiation resistance associated with radiotherapy by alleviating tumor hypoxia,but also down-regulated glutamine synthetase to inhibit the DNA damage repair system.In the postoperative radiotherapy model of cancer,the nanocomposites showed an excellent anti-tumor effect,with a tumor inhibition rate of up to 89.8%.