Construction Of Multifunctional Nanoparticles Based On Hollow Mesoporous Silica Spheres For Enhanced Tumor Photodynamic Therapy

The malignant tumor is one of the major diseases threatening human life and health.In addition to the traditional surgery,chemotherapy,radiotherapy,and other tumor treatment methods,photodynamic therapy(PDT)is gradually developing into an effective adjuvant therapy.PDT is a treatment based on the interaction of photosensitizer,oxygen,and light to ablate tumors.PDT has the advantages of being non-invasive,high selectivity,less toxic,and side effects.However,in clinical application,the efficacy of PDT is significantly reduced due to the low transport efficiency of photosensitizer,skin phototoxicity,and insufficient oxygen supply in the tumor.In view of the shortcomings of PDT,hollow mesoporous silica nanoparticles(HMSNs)were used as nanocarrier platforms to construct multifunctional nanoparticles by loading photosensitizer and oxygen-carrying material inside,growing light-proof shell on the surface,and coupling metal ions,to enhance the therapeutic effect of tumor PDT.The main research contents are as follows:(1)Two kinds of hollow mesoporous silica nanoparticles with a positive charge(p-HMSNs)and negative charge(n-HMSNs)were designed and synthesized.The main factors affecting the drug loading efficiency were studied,which laid the foundation for constructing multifunctional nanoparticles.Firstly,HMSNs were prepared by the two-step method.The particle size,morphology,composition,and microstructure of p-HMSNs and n-HMSNs were analyzed by transmission electron microscopy,nanoparticle size analyzer,Fourier transform infrared spectroscopy,and specific surface area and aperture analyzer.It is found that the pore size of p-HMSNs and n-HMSNs are the same(?4 nm),but they have different particle sizes(?65 nm;?54 nm),cavity diameter(?57nm;?36 nm),and surface potential(34 m V;-14 m V).Then,three kinds of organic molecules were selected for drug loading,and the drug loading efficiency of HMSNs by different loading methods was studied.The results show that oil molecules can be effectively loaded into n-HMSNs and p-HMSNs by vacuum pumping method,and the loading efficiency is proportional to the cavity diameter;hydrophobic molecules can be loaded by capillary action,but the drug loading efficiency is low in both of them;water-soluble molecules can be loaded efficiently under the synergistic effect of electrostatic adsorption and capillary action,and the loading efficiency is higher in HMSNs with opposite electric properties.(2)Aiming at tumor hypoxia,a kind of oxygen self-carrying nano photosensitizer was designed and synthesized based on p-HMSNs,which enhanced the efficacy of PDT under hypoxia conditions at the cellular level.Firstly,to prepare oxygen self-carrying nano photosensitizers(PFH@NPSs)targeting tumor cells,p-HMSNs were functionalized with polyethylene glycol functionalized folic acid and then loaded with photosensitizer of protoporphyrin sodium salt(NAPP)and oxygen carrier of perfluorohexane(PFH).Based on the singlet oxygen quantum yield,the loading rate of NAPP was optimized,and the optimal ratio was 5 wt.%.The oxygen-carrying capacity and singlet oxygen production efficiency of PFH@NPSs were evaluated.The oxygen-carrying capacity is about 5.26 mg/g,and the singlet oxygen yield is about 4.4 times as much as that of non-oxygen-carrying nano photosensitizers(NPSs)under hypoxia conditions.PDT was performed on tumor cells under hypoxic conditions,PFH@NPSs.The inhibition rate of NPSs to tumor cell activity was 56.7%,while NPSs had almost no cytotoxicity.(3)Aiming at skin phototoxicity and tumor hypoxia problems,a multifunctional nanoparticle with skin safety was designed and synthesized based on p-HMSNs.The synergistic therapeutic effect of PDT-CDT on the tumor in mice was enhanced.Firstly,based on the mechanism of oxidative polymerization of dopamine triggered by singlet oxygen,the polydopamine(PDA)shell was grown on the surface of nano photosensitizers loaded with NAPP.Then,the multifunctional nanoparticles were prepared by folic acid functionalization and chelation of Fe²⁺.The effects of photosensitizer's concentration,light irradiation power density,and irradiation time on the polymerization of PDA were studied to optimize the shell thickness of PDA.Singlet oxygen production and cell phototoxicity under 405 nm and 638 nm light irradiation were analyzed to determine the properties of the nanoparticles for both skin safety(weak light was impenetrable)and phototoxicity(strong light was impenetrable).Then,the photothermal effect of the nanoparticles irradiated by 808 nm was studied,the generation rate of hydroxyl radical in Fenton reaction of Fe²⁺and H₂O₂was evaluated,and the cytotoxicity of CDTwas analyzed.Finally,the constructed multifunctional nanoparticles were used to treat tumor-bearing mice.Compared with the single-mode therapy,the inhibition rate of PDT-CDT synergistic treatment on tumor growth was 73.9%,which significantly enhanced the therapeutic effect of the tumor.