Fabrication Of Controlled Drug Release Systems Based On Photoresponsive Silica And Their Antitumor Efficacy

As one of the diseases with the highest mortality rate,cancer seriously threatens the health of human beings.With the development of novel therapeutic ways,the strategies combining multiple treatments have more advantages in improving the tumor inhibition rate and reducing the side effects on normal tissues/cells.Mesoporous silica has been widely used in biomedical diagnosis and drug delivery due to its good biocompatibility,adjustable particle size and huge specific surface area.In particular,multi-mode collaborative therapy based on the core-shell mesoporous silica combines the advantages of different materials and low drug toxicity.This thesis focuses on the biological application of mesoporous silica nanomaterials functionalized by phospholipid bilayer and natural erythrocyte membranes,aiming at design and construction of nanocarriers based on functionalized mesoporous silica composites and efficient loading of chemotherapeutic drugs/photosensitizers.Meanwhile,the magnetism,photothermal effect and optical properties of the nanocarriers were also used to realize synergistic treatment of chemotherapy-photothermal/photosensitivity of tumor cells.The main contents are as follows:In view of low sensitivity and complicated process of photo-controlled drug release nano-valve,a simple and highly sensitive nano drug loading system with phospholipid bilayer membrane as the photo-controlled nano valve is constructed.Firstly,gold nanorods with different aspect ratios are prepared by seed induced growth.The mesoporous silica coated gold nanorods is synthesized by utilizing cetyltrimethylammonium bromide as stabilizer and template,which is used for the loading of water-soluble chemotherapy drug doxorubicin.After the phospholipid bilayer is modified on the surface of mesoporous silica,the composite nanocarrier is obtained.Under near infrared irradiation(808 nm),gold nanorods can convert near infrared light into heat.With the increase of temperature,the permeability of phospholipid bilayer membrane improved,which is conducive to the release of DOX.After stopping the illumination,the permeability of phospholipid bilayer membrane reduced,which prevents from the release of DOX.This process is reversible.The drug carrier shows a significant inhibitory effect on tumor cells through the synergistic effects of photothermal and chemotherapy.Aiming at the problems of poor targeting of nanocarriers and uncontrolled drug release in tumor cells,a magnetic targeting nanocomposite system with temperature and p H sensitive phospholipid molecules as nanovalves is prepared.A variety of Fe3O4 nanoparticles with different particle sizes are prepared by co-precipitation method,solvothermal method and thermal decomposition method.The diameter of water-soluble Fe3O4 nanoparticles prepared by co-precipitation method is about 20 nm.But they are prone to form agglomeration.The water-soluble Fe3O4 nanoparticles with diameters of about 240,130 and 35 nm are prepared by solvothermal method by adjusting the amounts of sodium citrate.The Fe3O4 nanoparticles prepared by this method have uniform particle sizes and good dispersions.However,serious agglomeration occurrs after silica coating.The "eukaryotic cell" structure nanocomposites are prepared using oleic acid-modified Fe3O4 nanoparticles with a diameter of about 20 nm as the cores,mesoporous silica as the basic skeleton,and phospholipid as the membrane.Their specific surface area is 625 m2 g-1,and can effectively load DOX(Drug loading rate 31.9 ± 4.5%).Fe3O4 nanoparticles can realize photothermal treatment after absorbing near-infrared light,and achieve the precise release of DOX at tumor specific location through lipid "switch" with temperature and p H sensitivity,so as to achieve the synergistic effect of photothermal chemotherapy.Aiming at the limited drug loading rate of single mesoporous silica nanoparticles,graphene based mesoporous silica nanocomposites with “sandwich” structure is prepared,with phospholipid membrane on the surface for improvement the biocompatibility,and water solubility.Aromatic chemotherapeutic drug doxorubicin is loaded into the pores of silica layer via electrostatic and ?–? interactions with high loading rate 53.3 ± 2.9%,which could effectively reduce the amount of nanocarrier.The controlled drug release from the nanocarrierswas is realized by using their inherent near-infrared strong absorption and thermal responsiveness of phospholipid bilayer.In vivo anti-tumor studies in nude mice have shown that chemotherapy can slow down the growth of tumors.The tumors are ablated at the initial stage of photothermal therapy,but relapse after 7 days.After cooperating with photothermal chemotherapy,the tumor tissue disappears without recurrence within 15 days.The body weight changes in nude mice and the H&E staining results of the main organs show that the carriers have no obvious toxic and side effects on normal organs.Targeting the problem of immune clearance during the transportation of nanocarriers,the erythrocyte membrane is used to camouflage the rare earth coreshell structure of upconversion nanoparticles.An immune evasion nanocarrier system is constructed,which realized the cooperative treatment of chemotherapy and photodynamic therapy.The rare earth upconversion nanoparticles camouflaged with erythrocyte membrane promotes good biocompatibility and immune evading ability.Quantitative analysis by flow cytometry shows the fluorescence intensity of the unmodified nanoparticles in the macrophage is 2.58 times that of the modified ones.The photosensitizer chlorin e6(Ce6)is fixed in the mesoporous silica shell through hydrolysis and cocondensation,which effectively avoids the leakage and agglomeration of the photosensitizer.Under the irradiation of 980 nm laser,up conversion nano particles can convert nearly infrared light into 660 nm visible light which can be absorbed by Ce6,thereby generating singlet oxygen(1O2),which not only is used for photodynamic therapy,but also achieves accurate DOX release.The results show that the cell death rate of photodynamic/chemotherapy is respectively 1.3 times and 1.5 times higher than those of chemotherapy and photodynamic therapy.