新型树枝状大分子造影剂的制备与生物成像研究
[Abstract]:Tumor imaging is an important technique in the diagnosis of tumor. At present, the magnetic resonance imaging (MRI) is widely used in the imaging technology of human body tumor, which has the advantages of no radiation, no wound and high resolution of soft tissue, and provides great help for the progress of the diagnosis technology of the tumor. However, the imaging sensitivity of the MRI to the tumor is not ideal, and the contrast of the tumor imaging need to be enhanced using the contrast agent. At present, most of the contrast agent used clinically is a small molecular weight complex, the structure is simple, the safety is good, the relaxation rate is low, the clearing speed is too fast, the tumor targeting property is short, and the requirement of the clinical diagnosis of the tumor can not be met. Therefore, it is urgent to develop a new contrast agent with high relaxation rate, long circulation and tumor targeting, and to improve the sensitivity of MRI to the diagnosis of tumor. The combination of the nano-carrier and the MRI contrast agent can improve the relaxation and the targeting performance of the contrast agent. In various kinds of nano-carriers, the dendritic macromolecule has the advantages of clear structure, uniform distribution and many surface groups, and is an ideal nano-carrier material. However, the present dendrimers have the problems of complex synthesis, poor biocompatibility and lack of anti-protein adsorption ability, which are easy to be removed by the reticuloendothelial system, and the application of them as the biological carrier material is limited. By using the multi-functional compound cyclodextrin as a core, two novel polyglycerol dendritic macromolecules and internally hydroxylated dendritic macromolecules are constructed, and the problem of difficult synthesis of the high molecular weight dendritic macromolecules is solved, and through the introduction of the zwitterionic and tumor targeting groups which avoid non-specific adhesion, the tumor-targeted dendritic macromolecular contrast agent is obtained. First, a 1-4 generation of polyglycerol dendrimer CPGD was synthesized by the alternate Willis and Sharpless reaction, and 1H NMR and gel n were used as the monomer to synthesize the 1-4-generation polyglycerol dendrimer CPGD. The structure of ALTI-TOF-MS was characterized. The dendritic macromolecule has the advantages of stable structure and good biocompatibility by using the glycerol ether as a structural unit. The molecular weight of the dendrimer increased from 5.1kDa to 18.9 kDa, and the surface functional group increased from 48 to 168. The dendrimers with different groups of hydroxyl group, amino group, alicyclic group and zwitterionic group are synthesized through the reaction of the dendrimer with the double-bond group and the compound of the different groups of polar groups, and the toxicity of the groups on the surface and the interaction with the protein is studied. The effect of the endocytosis and the distribution of the organ found that the CPGD with the amino group on the surface was too toxic and the bio-compatibility was poor. The GGD with the donor base was more widely distributed in the tumor, but the cytotoxicity was large and it was not easy to enter the cell. and the zwitterionic CPGD does not interact with the protein under normal pH 7.4, and interacts with the protein under the acidic pH of the tumor, and can escape from the acid lysosomes and has better tumor drug/ contrast agent delivery performance. then, a contrast agent molecule is introduced on the surface of the zwitterionic polyglycerol dendrimer, and the obtained polyglycerol dendrimer contrast agent is obtained. The relaxation rate of CPGD-G3-DOTA-Gd is 14. 3mM ~ (-1) s ~ (-1), which is about 3. 3 times of Magnitude. The zwitterionic modified polyglycerol dendrimer contrast agent can obviously reduce the endocytosis of the cells and can be used as the residual of the contrast agent of the extracellular contrast agent in the body. The in vivo imaging of ICR mice has proved that the contrast agent has a good blood pool contrast ability, and the relative Magnitude can maintain the enhancement effect on the blood pool in a long time, and also has better enhancement effect on the blood vessel-rich organs, wherein the high-algebra dendrimer contrast agent phase has a longer in-vivo circulation time and better contrast effect than the low-algebra, and the contrast agent has little long-term treatment, so that the systemic toxicity caused by the retention and the metabolism of the contrast agent can be avoided. In addition, on the surface of the polyglycerol dendrimer contrast agent, the tumor anaerobic targeting group is introduced through the PEG link, the tumor-targeted dendritic macromolecular contrast agent is obtained, the relaxation rate is 6-9 times of the Magnitude, and can be enriched in the hypoxic region of the tumor, and the contrast between the tumor and the normal region is obviously enhanced. in that end, to avoid the introduction of contrast agent on the surface of the dendrimer to destroy the zwitterionic property of the dendrimer. In this paper, a kind of internally hydroxylated dendrimer was synthesized by the open-loop reaction and the "thiol-allyl" reaction of the "amine-epoxy", and the structure of the dendrimer was characterized by ~ 1H NMR and gel permeation chromatography. At the same time, the contrast agent is connected to the inside of the dendritic macromolecule, and a zwitterionic and tumor-targeted sulfanilamide group is introduced on the surface of the dendrimer, so that a novel tumor targeting dendritic macromolecular contrast agent is obtained. in which, the zwitterionic can avoid the non-specific protein adhesion and the endocytosis, and the tumor targeting group on the surface can mediate the tumor cell specific endocytosis of the dendritic macromolecular contrast agent and improve the tumor targeting performance of the contrast agent. The particle size of the contrast agent is about 6.2nm, the relaxation rate is 11. 3mM-(-1) s-(-1), which is about 2.7 times of Magnitude. The cell experiment shows that the contrast agent has the tumor anaerobic targeting performance, and the animal experiment shows that the tumor targeted dendritic macromolecular contrast agent obviously enhances the magnetic resonance imaging of the tumor and can be quickly discharged out of the body through the kidney without obvious systemic toxicity, is an ideal tumor-targeting contrast agent.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ421.7
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