pH响应的抗原和免疫激动剂共载体系的构建及其抗肿瘤免疫治疗研究

发布时间：2018-05-26 21:36

本文选题：免疫治疗 + 金属有机框架　；参考：《河北大学》2017年硕士论文

【摘要】：由于纳米载体能够提高肿瘤相关抗原(TAAs)被抗原呈递细胞的摄取率,因此,基于纳米载体肿瘤免疫治疗策略被认为是非常有前景得治疗手段。然而,目前的肿瘤相关抗原装载手段太过复杂,而且其负载率并不理想,更重要的是,基于纳米载体的肿瘤免疫治疗策略往往无法有效的活化CD8+T淋巴细胞,从而导致较低的肿瘤治疗效果。因此,发展一种更为理想的肿瘤相关抗原运载体系,对于抗肿瘤的免疫治疗具有重大的意义。本论文中,制备了一个结构简单但功能强大的基于pH响应的金属有机框架(MOFs)。通过一步法直接将TAA装载到金属有机框架纳米材料中,在溶酶体的酸性环境中,由于金属配体键不稳定,MOFs纳米材料发生降解;从而促进纳米材料从内涵体/溶酶体中逃逸,进而增加抗原的交叉呈递。此外,未甲基化的胞嘧啶核苷酸-鸟嘌呤核苷酸(CpG)通过Watson Crick碱基配对与MOFs中的鸟苷三磷酸腺苷(GMP)结合,CpG能够进一步增强CD8+T细胞的活性。实验结果表明,MOFs共载抗原和佐剂的合成方法非常简单、方便、有效,在体外和体内实验结果均表明共载体系无明显毒性。该方法具有较高的抗原负载能力,最大抗原包封率约为55%(w/w)。此外,我们建立了B16-OVA的小鼠荷瘤模型,结果显示,给予pH响应的共载体系治疗的小鼠的肿瘤得到很好的抑制(100%存活)。最后,我们通过对肿瘤组织进行免疫组化分析,表明共载体系治疗的肿瘤组织发现大量的杀伤性细胞毒性T淋巴细胞的浸润,证明抗肿瘤的作用是激活免疫应答产生的。本文结果表明,构建的具有pH响应溶酶体逃逸能力的共载体系能够通过诱导细胞免疫对癌症进行治疗。
[Abstract]:Because nano-carriers can increase the uptake rate of TAAs-based antigen-presenting cells, the strategy of tumor immunotherapy based on nano-carriers is considered to be a promising therapeutic method. However, the current tumor associated antigen loading methods are too complex, and their loading rate is not ideal. More importantly, the tumor immunotherapy strategy based on nano-carrier is often unable to effectively activate CD8 T lymphocytes. As a result, the effect of tumor therapy is low. Therefore, the development of a more ideal tumor-associated antigen delivery system is of great significance for anti-tumor immunotherapy. In this thesis, a simple and powerful organometallic framework based on pH response was prepared. TAA was directly loaded into organometallic framework nanomaterials by one step method. In the acidic environment of lysosomes, the metal ligand bonds were unstable and the nanomaterials were degraded, thus promoting the escape of the nanomaterials from the connotations / lysosomes. Furthermore, cross-presentation of antigens is increased. In addition, unmethylated cytosine nucleotide-guanine nucleotides (CPG) can further enhance the activity of CD8 T cells by Watson Crick base pairing with adenosine triphosphate (ADP) in MOFs. The experimental results show that the method of synthesis of MOFs cocarrier antigens and adjuvants is very simple, convenient and effective. The results of both in vitro and in vivo experiments show that there is no obvious toxicity of the co-loaded antigens and adjuvants. The method has high antigen loading capacity and the maximum antigen encapsulation efficiency is about 55 w / w. In addition, we established a mouse tumor bearing model of B16-OVA. The results showed that the tumor of mice treated with pH-responsive co-carrier system was well inhibited by 100% survival. Finally, by immunohistochemical analysis of tumor tissues, we found that a large number of cytotoxic T lymphocytes were infiltrated in tumor tissues treated with co-carrier system, which proved that the anti-tumor effect was caused by activation of immune response. The results showed that the co-loaded system with the ability to escape from lysosomes in response to pH could be used to treat cancer by inducing cellular immunity.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R730.51;TB383.1

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