基于介孔有機(jī)氧化硅的腫瘤多模式成像及其引導(dǎo)下的增效治療
[Abstract]:Traditional methods of tumor therapy have limitations, such as the strong toxic and side effects of chemotherapy, and the spent oxygen environment in tumors also inhibits the effect of radiotherapy. The application of nano-materials in biomedicine provides a new method for diagnosis and treatment of tumor, which can combine multiple imaging methods with the treatment mode. "Integration of diagnosis and treatment" The combination of imaging and therapeutic capabilities with the same nanomaterials has been widely used in drug delivery tracing, treatment effectiveness monitoring, and imaging guided therapy. The mesoporous organic silicon oxide nano-particles have good dispersibility, uniform size, large specific surface area, biodegradability and high biocompatibility, and is an ideal carrier of the tumor diagnosis and treatment system. In this paper, a systematic study on the diagnosis and treatment of tumor diagnosis and treatment based on mesoporous organic silicon oxide is carried out, which mainly includes the following three aspects: 1. the mesoporous organic silicon oxide diagnosis and treatment integration system is used for constructing a periodic egg yolk-eggshell structure mesoporous organic silicon oxide (PMOP) based on a thioether bond for tumor target imaging and synergistic chemotherapy, The surface stably connects the near-infrared fluorescent molecule Cy5. 5 with the affinity body of the target human epidermal growth factor receptor-2 (Her2) so as to have the capability of near-infrared fluorescence imaging and targeting Her2 positive tumor cells. With the structure of the sulfide bond in the nano particle framework, the chemotherapy drug adriamycin (DOX) loaded in the cavity can be released in response to the action of glutathione (GSH) in the tumor cells. The amount of drug released within 24h of 10mM GSH solution can reach 84.8%, which is more than double the release amount under the condition of GSH-free stimulation. In addition, the release of drug in 24 h in neutral environment (pH 7.4) was 31.7% in neutral environment (pH 7.4), while the release amount of pH 5.0 was 53.6% in acidic environment (pH 5.0). Laser confocal scanning microscope and cell-flow analysis show that the diagnosis and treatment system can target Her2-positive tumor cells efficiently and can be taken up, thereby effectively killing tumor cells. At the same time, Cy5.5 has good near infrared fluorescence imaging capabilities to monitor the distribution, delivery, and release of intracellular drugs. At the same time, the cell experiment and pathological section of animal organ tissue show that the diagnosis and treatment integration system has good biocompatibility and lays a good foundation for the subsequent biological application. In summary, this study has developed a novel tumor cell targeting imaging and synergistic chemotherapy system with targeted tumor cells, near infrared fluorescence imaging, and GSH/ pH dual response drug release capabilities. secondly, the three-response degradable mesoporous organic silicon oxide thermal treatment integrated system is used for the combination therapy of hyperthermia and chemotherapy and chemotherapy, and the combination therapy can greatly improve the treatment effect of the tumor. This study suggested that the warming effect could enhance the efficacy of chemotherapy, and discussed the mechanism of synergistic treatment in vitro and in vivo tumor model. The invention discloses a novel biodegradable diagnosis and treatment integrated system based on a human body, a periodic egg yolk-eggshell structure and a mesoporous organic silicon oxide (CuS @ PMOs), which is used for photothermal conversion and drug delivery. The prepared CuS @ PMOP has strong chemotherapeutics DOX loading capacity, and the release of DOX is up to 470 mg/ g. The release of DOX can be controlled accurately by triple stimulation, including high concentration of GSH in tumor cells, acidic environment in tumor and external laser irradiation. The experimental results show that the hyperthermia produced by laser irradiation greatly improves the tumor cells in vitro and the uptake of nano-particles in body tumors, thus remarkably enhancing the curative effect of chemotherapy, and completely inhibiting the growth of the tumor. Meanwhile, the fluorescence imaging capability of DOX itself can be used to monitor drug delivery and release. Three, thermoresponsive perfluoropentane gasification is a key to solving the problem by finding a way to efficiently deliver oxygen to a tumor region due to a spent oxygen environment of a synergistic radiotherapy tumor for a spent oxygen tumor. Perfluoropentane (PFP) has a strong affinity for oxygen, the boiling point in the body is 40-50 DEG C, and a delivery system based on hydrogen cyanide, hollow mesoporous organic silicon oxide nanoparticles (HMON @ CuS) is constructed, and PFP (O2-PFP @ HMON @ CuS-PEG) carrying oxygen is delivered to the tumor area for synergistic radiotherapy of the spent oxygen tumor. The heat generated by the CuS after laser irradiation can cause the PFP to generate liquid-gas phase change, the generated bubbles can not only enhance the ultrasonic imaging signal, but also promote the rapid release of oxygen, promote the diffusion of oxygen in the spent oxygen tumor, The cell experiment proves that the method can greatly enhance the radiotherapy curative effect of the spent oxygen tumor cells. The distribution of nano-particles in mice can be observed by positron emission tomography (PET) imaging. The experimental results show that the nanoparticles have a long half-life of blood, and after 24 hours after intravenous injection, the peak is reached in the tumor area. and may continue to 48 h. Alternatively, the CuS also has an optical acoustic (PA) imaging capability. Therefore, under the stimulation of the near infrared laser, the integrated system of the diagnosis and treatment can realize the synergistic radiotherapy aiming at the spent oxygen tumor under the precise image guidance of the PET/ ultrasonic/ optical sound three modes, and has good clinical application prospect.
【學(xué)位授予單位】:南京大學(xué)
【學(xué)位級(jí)別】:博士
【學(xué)位授予年份】:2017
【分類號(hào)】:R730.5
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