Studies On The Construction Of TiO₂-based Nanocomposites And Their Applications In Visualization Of Breast Cancer Therapy

Breast cancer is the most common malignancy in women.With the development of nanoscience,titanium dioxide（TiO₂）nanoparticles with good biocompatibility and excellent photocatalytic activity have been widely applied in study of drug delivery and ultraviolet triggered phototherapy of breast cancer.At present,there are two urgent problems in TiO₂ based breast cancer therapy:1)as drug carrier,how to overcome the multidrug resistance of breast cancer as well as achievement of low toxicity and high efficiency therapy in vivo;2)how to overcome the bottleneck of TiO₂ based phototherapy,which requires ultraviolet as exciting light.In this dissertation,to solve these problems,a series of TiO₂ nanocomposites are constructed and innovatively used to overcome multidrug resistance of breast cancer cells,systemic administration,808 nm near infrared light triggered visual photothermal therapy and synergistic therapy.The main research contents are as follows:1)Construction of white TiO₂-DOX nanocomposites and in vitro study of treatment in multidrug-resistant breast cancer.In this study,anatase TiO₂nanoparticles were prepared by sol-gel method.Then Doxocibine（DOX）was loaded onto TiO₂ by electrostatic adsorption to form TiO₂/DOX nanocomposites.The optimal stability of the nanocomposites was achieved by regulating drug loading rate（0.5%）and the nanocomposites were used in the treatment of drug-resistant breast cancer cells MCF-7/ADM.The results showed that the prepared nanocomposites were pH-responsive drug carriers.After the nanocomposites were invaginateed into lysosomes（pH 4-5）,the drugs were released from TiO₂ and transfered into nucleus,thus avoiding the drug efflux by P-glycoprotein on cell membranes and therefore increasing drug accumulation in nucleus.In vitro results showed that TiO₂/DOX exhibited more effective inhibition of MCF-7/ADM cell activity,which was 2.4 times higher than that of DOX alone.Therefore,as-prepared TiO₂/DOX nanocomposites are expected to overcome the multidrug resistance of breast cancer cells.2)White TiO₂-PEG-DOX nanocomposites enhance chemotherapy in orthotopic breast tumor bearing mouse model.As a key stage before clinical study,the effectiveness of TiO₂-PEG-DOX in tumor bearing mouse has not been proved.Based on the previous work,to improve the stability in physiological environment and reduce the removal by macrophages,TiO₂ nanopartieles were coated with PEG.Then DOX were loaded onto TiO₂ to form TiO₂-PEG-DOX nanocomposites.The characterization results of nanocomposites showed that the nanocomposites coated with PEG could release about 80%of the drugs at pH 5.Then vivo treatment showed that TiO₂-PEG-DOX not only enhanced the anti-tumor effect,but also reduced the systemic toxicity of drugs.This study is the first time to confirm the good therapeutic effect of TiO₂ carrieres on animal model,which lays an experimental foundation for further development of TiO₂ based highly efficient,low toxicity,controllable drug carrieres and their possible clinical application.3)Construction of black TiO₂-PEG nanocomposites and study of photothermal therapy of breast cancer triggered by 808 nm near infrared light.Aimed at the limitations of ultraviolet light（mutation inducer and tissue penetration only⁰.8 mm）as excitation for photodynamic therapy of white TiO₂,we have firstly developed the near infrared light-triggered black TiO₂ nanoparticles for photothermal therapy of tumors.The experimental results showed that the non-radiative recombination caused by the large amount of Ti³⁺deep level defects is the mechanism of the photothermal effect of black TiO₂.In order to improve the stability of black TiO₂ in vivo,reduce toxicity and avoid uptake by macrophages,black TiO₂ nanoparticles were coated with PEG to form black TiO₂-PEG nanocomposites.In vitro and in vivo results showed that the photothermal conversion efficiency of the prepared black TiO₂-PEG was as high as 40.8%.The nanocomposites completely ablated the tumors of breast cancer model mice under irradiation of 808 nm near infrared,and significantly prolonged the survival period of the tumor-bearing mice.This work breaks through the problem of ultraviolet triggered cancer treatment of TiO₂,and promotes the further development of the TiO₂ based diagnosis and treatment of cancer.4)Construction of black TiO₂-based core-shell nanocomposites and its visualized photothermal-chemotherapeutic synergistic therapy for breast cancer.Based on the previous works in this dissertation,the core-shell structure nanocomposites of black TiO₂@mSiO₂ were designed and fabricated.The nanocomposites were loaded with DOX for thermal imaging-guided photothermal-chemotherapy of breast cancer which was triggered by 808 nm near infrared.The results showed that the drug loanding rate of black TiO₂@mSiO₂ was5%,which is 10 times higher than that of black TiO₂ alone（0.5%）.The drug release rate reached 91.3%under weak acid environment and near-infrared photothermal effect.Meanwhile,the nanocomposites showed a good synergistic effect of photothermal and chemotherapy on breast cancer cells and tumor-bearing mice models.The above results indicated that as-prepared black TiO₂@mSiO₂ core-shell nanocomposites not only overcome the defect of low drug loading rate of TiO₂-based nanocarriers,but also improve the incomplete treatment caused by the uneven distribution of near infrared light in tissues.