一种两亲性嵌段共聚物放疗增敏剂的制备和应用

发布时间：2018-03-27 21:45

本文选题：嵌段共聚物　切入点：点击化学　出处：《中国科学技术大学》2017年硕士论文

【摘要】：近年来放射治疗已经成为目前肿瘤治疗的主要手段之一,放射治疗的效果显著,据估计,有接近70%的癌症患者愿意选择接受放射治疗来治疗癌症。目前,肿瘤放射治疗领域的主要难题是如何应对乏氧肿瘤细胞的辐射抗性。由于高能的射线在辐照肿瘤的同时也会对正常组织有所影响,可能造成正常组织的严重损伤,因此不可能通过持续提高辐射剂量来杀死缺氧的肿瘤细胞。研究发现使用合适的放疗增敏剂可以有效的提高对恶性肿瘤的放疗效果,同时还能显著的降低放疗所需的辐射剂量,进而避免了对正常组织的损伤。本文主要研究了一种新型的两亲性嵌段聚合物放疗增敏剂。与小分子放疗增敏剂相比,不仅具有更高的增敏增强比,而且更稳定,还能有效的富集在肿瘤部位从而显著的提高放射治疗的效果。这种聚合物放疗增敏剂可以通过简单高效的化学反应来合成,进而通过在水中自组装制备。为了进一步研究了聚合物胶束的放疗增敏效果,本文还分别在细胞层面和小鼠肿瘤模型层面上对聚合物胶束的放疗增敏效果进行了评估。本论文的研究内容以及主要结论如下:1、本文首先合成和制备了聚合物胶束。先将谷氨酸的一端羧基与丙炔醇反应修饰上炔基,又通过使用单端氨基聚乙二醇单甲醚作为引发剂,引发了谷氨酸丙炔酯的开环聚合反应,并得到了聚乙二醇-b-聚谷氨酸丙炔酯。通过一系列有机化学反应将甲硝唑末端的羟基转变成了叠氮基团。最后使用点击化学将两种分子结合在一起,并最后终得到了单分散性的聚乙二醇-b-(聚谷氨酸-g-甲硝唑)。两个嵌段的聚合度分别为113和60。将其溶于少量乙腈并加入水中,浓缩有机溶剂后可以得到聚合物胶束纳米粒子。聚合物胶束粒径约为60 nm,并具有很好的稳定性。2、其次,为了从细胞层次上研究聚合物胶束的生物相容性和放疗增敏性能,本文将聚合物胶束直接作用于细胞,并使用X射线进行放射治疗。研究结果发现,聚合物胶束在被细胞摄取后并未产生明显的毒性;在接受X射线照射处理过后,乏氧的细胞的存活率大幅降低,并且表现出比小分子放疗增敏剂更加优异的增敏效果。3、最后通过建立小鼠肿瘤模型研究了聚合物胶束在生物体内的分布以及配合放射治疗的抑瘤效果。结果表明聚合物胶束能够在短时间内富集到肿瘤部位并且稳定的存在;配合放射治疗后能够表现出显著的抑瘤效果并且对正常器官组织不会造成任何损伤。
[Abstract]:In recent years, radiation therapy has become one of the main means of current cancer treatment, radiation treatment effect is remarkable, it is estimated that nearly 70% of the cancer patients are willing to choose to accept radiation therapy to treat cancer. At present, the main problems of tumor radiotherapy field is how to deal with the radiation resistance of hypoxic tumor cells. At the same time due to high-energy radiation the tumors were also affected the normal tissue, may cause serious damage to normal tissue, it is not possible through continuous improvement of radiation dose to kill the tumor cells. The study found that hypoxia can effectively improve the efficacy of radiotherapy for malignant tumor using suitable radiation sensitizer, and can significantly reduce the radiation dose of radiotherapy need, and avoid the damage to normal tissue. This paper mainly studies a new type of amphiphilic block copolymer two radiosensitizer and small. Sub radiosensitizer compared, not only has the higher sensitizing enhancement ratio, and more stable, but also can effectively improve the radiation to significantly enriched in the tumor therapy. This polymer radiosensitizer can be synthesized by chemical reaction is simple and efficient, and through self assembling in water for preparation. Radiotherapy is further studied polymer micelle sensitization effect, this paper at the level of cell level and tumor model mice on radiotherapy on polymer micelle sensitization effect was evaluated. The research contents of this thesis and the main conclusions are as follows: 1. Preparation of polymeric micelles firstly, synthesis and system. The first end carboxyl and propargyl the reaction of alcohol modified glutamate alkynyl, and through the use of a single amine terminated polyethylene glycol monomethyl ether as the initiator, led to the ring opening polymerization of glutamic acid propargyl ester, and poly ethylene glycol -b was obtained Polyglutamic acid propargyl ester. Through a series of organic chemical reaction will change at the end of the metronidazole hydroxyl azide groups. Finally using click chemistry two molecules together, and finally get the monodisperse polyethylene glycol -b- (poly glutamic acid -g- metronidazole). Two block polymerization degree respectively. 113 and 60. will be dissolved in a small amount of acetonitrile and adding water, concentration of organic solvent can be obtained after polymer micelle polymer micelle nanoparticles. The particle size is about 60 nm, and has very good stability of.2. Secondly, in order to study the polymeric micelles from the level of cell biocompatibility and radiation sensitizing properties, the polymer micelle a direct effect on the cell, and radiation therapy using X ray. The results of the study showed that the polymer micelles did not produce significant toxicity in cellular uptake; in an X ray irradiated after hypoxia The survival rate of cells significantly reduced, and showed than small molecule radiosensitizer more excellent sensitizing effect of.3, the distribution model of micelles was studied in vivo in mice tumor and radiotherapy combined with the inhibitory effect. The results show that the polymer micelles can in a short period of time to the tumor site and enrichment there were stable; combined with radiotherapy can show significant antitumor effect and no damage to normal tissues.

【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;O631

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