Application Of Phthalocyanine - Modified Mesoporous Silica In Multimode Imaging And Synergistic Therapy

Over the past decade, cancers have become one of the major causes of mortality in the world. Current clinical therapy methods, including radiation therapy, chemotherapy, hormone therapy and immunotherapy, are often associated with severe side effects. Owing to the convenience and minimal invasiveness, phototherapy, including photodynamic therapy(PDT) and photothermal therapy(PTT), is emerging as a powerful technique for cancer treatment. To date, however, few examples of combined PDT and PTT have been reported. Phthalocyanine(Pc) is a class of traditional photosensitizer for PDT, but its bioapplication is limited by high hydrophobicity. In present study, silicon dihydroxyl phthalocyanine(SPCD) with Si-OH was selected to modify the silica surface by the hydrolysis of Si-OH, and the water soluble phthalocyanine-containing nanocomposite was obtained by further modification of hyaluronic acid(HA) or PEG. The as-prepared nanocomposite exhibits highly efficient dual PDT and PTT effects. In vitro and in vivo experimental results clearly indicated that the dual phototherapeutic effect of SiO 2-SPCD can kill cancer cells or eradicate tumor tissues. There are four chapters in this thesis.In the first chapter, we first summarized the therapeutic mechanism of optical therapy, the common optical therapeutic agents and the application of optical therapy in nanotechnology. Then the basic properties and applications of phthalocyanine are briefly introduced. At last, the idea of this thesis is prosed.In the second chapter, Ba Gd F5 nanoparticles were synthesized by solvothermal method, and then coated with mesoporous silica by sol-gel method to produce Ba GdF5@m SiO2. Then, the photosensitizer SPCD and targeted agent HA were modified one after another on the SiO2 surface. The synthesized nanocomposite was in good morphology. The prepared BaGd F5@m SiO2-SPCD/HA held good solubility and can be stably dispersed in several physiological solutions. The in vitro experiments demonstrated that Ba GdF5@mSiO2-SPCD/HA had low cytotoxicity and it could specifically target He La cells which overexpressed CD44 to kill the cancer cells by photodynamic/ photothermal therapy. In vivo targeted synergistic therapeutic effect was also significant. BaGd F5@m SiO2-SPCD/HA has good in vivo therapeutic effect and low toxicity. Due to the presence of Gd and Ba elements, Ba GdF5@m SiO2-SPCD/HA showed ideal magnetic resonance(MR) contrast effect and X-ray attenuation property in cellular level or even in the tumor-bearing mice, which indicated that the obtained material is a promising multi-modal biological imaging contrast agent. Therefore, BaGdF5@m SiO2-SPCD/HA nanomaterials showed good targeted MR/CT imaging and PDT/PTT functions, and they have promising application potential in cancer diagnosis and treatment.In the third chapter, we firstly prepared and characterized a series of rare earth metal doped silica hollow nanovesicles. Then, the gadolinium doped silica hollow nanospheres were modified with SPCD and mPEG-Silane to produce the multifunctional HS-Gd-SPCD/PEG nanomaterials. Silica hollow nanospheres were prepared by hydrothermal method. SPCD and mPEG-Silane were modified on the silica surface by hydrolysis of Si-OH or silane. The as-prepared HS-Gd-SPCD/PEG showed uniform vesicle-like morphology and good solubility in water. The results of the synergistic therapy experiments and AM/PI double staining experiments using 4T1 cells showed that the HS-Gd-SPCD/PEG material had good phototherapeutic effect. Gd3+ has 7 non-paired electrons, high spin magnetic moment, electric field symmetry, and high relaxation rate. Meanwhile, the silica vesicles have excellent echogenic property. Therefore, HS-Gd-SPCD/PEG showed good contrast effect in MR and US imaging. HS-Gd-SPCD/PEG nanomaterials is expected to combine MR, US imaging and cancer PDT/PTT into one system, and such nanomaterials have good application prospect in the field of biomedicine.In the fourth chapter, we summarized the important experimental data and results obtained in this work. Finally, we showed the outlooks about the further applications of phthalocyanine modified silicananomaterials in the future.