發(fā)布時(shí)間：2018-05-26 21:36

  本文選題：免疫治療 + 金屬有機(jī)框架　； 參考：《河北大學(xué)》2017年碩士論文

【摘要】：由于納米載體能夠提高腫瘤相關(guān)抗原(TAAs)被抗原呈遞細(xì)胞的攝取率,因此,基于納米載體腫瘤免疫治療策略被認(rèn)為是非常有前景得治療手段。然而,目前的腫瘤相關(guān)抗原裝載手段太過復(fù)雜,而且其負(fù)載率并不理想,更重要的是,基于納米載體的腫瘤免疫治療策略往往無法有效的活化CD8+T淋巴細(xì)胞,從而導(dǎo)致較低的腫瘤治療效果。因此,發(fā)展一種更為理想的腫瘤相關(guān)抗原運(yùn)載體系,對(duì)于抗腫瘤的免疫治療具有重大的意義。本論文中,制備了一個(gè)結(jié)構(gòu)簡(jiǎn)單但功能強(qiáng)大的基于pH響應(yīng)的金屬有機(jī)框架(MOFs)。通過一步法直接將TAA裝載到金屬有機(jī)框架納米材料中,在溶酶體的酸性環(huán)境中,由于金屬配體鍵不穩(wěn)定,MOFs納米材料發(fā)生降解;從而促進(jìn)納米材料從內(nèi)涵體/溶酶體中逃逸,進(jìn)而增加抗原的交叉呈遞。此外,未甲基化的胞嘧啶核苷酸-鳥嘌呤核苷酸(CpG)通過Watson Crick堿基配對(duì)與MOFs中的鳥苷三磷酸腺苷(GMP)結(jié)合,CpG能夠進(jìn)一步增強(qiáng)CD8+T細(xì)胞的活性。實(shí)驗(yàn)結(jié)果表明,MOFs共載抗原和佐劑的合成方法非常簡(jiǎn)單、方便、有效,在體外和體內(nèi)實(shí)驗(yàn)結(jié)果均表明共載體系無明顯毒性。該方法具有較高的抗原負(fù)載能力,最大抗原包封率約為55%(w/w)。此外,我們建立了B16-OVA的小鼠荷瘤模型,結(jié)果顯示,給予pH響應(yīng)的共載體系治療的小鼠的腫瘤得到很好的抑制(100%存活)。最后,我們通過對(duì)腫瘤組織進(jìn)行免疫組化分析,表明共載體系治療的腫瘤組織發(fā)現(xiàn)大量的殺傷性細(xì)胞毒性T淋巴細(xì)胞的浸潤(rùn),證明抗腫瘤的作用是激活免疫應(yīng)答產(chǎn)生的。本文結(jié)果表明,構(gòu)建的具有pH響應(yīng)溶酶體逃逸能力的共載體系能夠通過誘導(dǎo)細(xì)胞免疫對(duì)癌癥進(jìn)行治療。
[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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R730.51;TB383.1

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本文編號(hào)：1938969