發(fā)布時間：2018-03-28 01:17

  本文選題：二硫鍵　切入點：自交聯(lián)　出處：《中國科學技術大學》2016年博士論文

【摘要】：腫瘤嚴重威脅著人類的健康甚至生命。傳統(tǒng)治療方法,主要包括化學療法和放射療法,由于副作用嚴重而最終治療效果有限�；蛑委熍c光熱治療是近年來備受關注的新型腫瘤治療方式,有望有效清除腫瘤、同時又不傷害人體正常組織,從而改善腫瘤治療療效、降低脫靶毒副作用。但是,基因治療與光熱治療系統(tǒng)還待改善,比如基因載體在體內不穩(wěn)定、光熱試劑在腫瘤的富集量較低等。在本論文中,我們在：(一)基因遞送系統(tǒng)的構建方面,利用二硫鍵的自交聯(lián),增加基因載體的穩(wěn)定性以及其在體內的轉染效率：(二)腫瘤光熱治療方面,構建了新型光熱納米系統(tǒng),從而改善了腫瘤光熱治療效率。(一)體內穩(wěn)定性更好的基因遞送系統(tǒng)：我們發(fā)現(xiàn)利用含有二硫鍵的聚酰胺鍵和DNA形成的復合物可以通過加熱在短時間之內使其交聯(lián),獲得了在生理條件下穩(wěn)定性更好、在含血清條件下和實驗小鼠體內轉染效率都更高的基因遞送系統(tǒng)。在此基礎上,我們通過加熱使超支化PEG在陽離子聚合物與DNA形成的復合物的表面形成保護殼層并通過二硫鍵的自交聯(lián)使其穩(wěn)定在復合物的表面,以形成一層可保護所得復合物系統(tǒng)不被血液中的蛋白所分解、但一旦進入細胞質可被谷胱甘肽降解的刺激響應性保護殼,實現(xiàn)DNA的可控釋放、提高基因轉染效率。(二)腫瘤治療更好的光熱納米顆粒：基于金納米籠和聚多巴胺這兩種光熱納米顆粒,我們構建了3種不同的腫瘤光熱治療系統(tǒng),以期改善治療效率。(1)金納米籠是一種近紅外光熱轉換納米顆粒,但其較短的體內循環(huán)時間限制了其在體內治療療效。我們將血紅細胞膜這種天然隱身材料包裹在金納米籠表面,構建了既有金納米籠的形貌、又有血紅細胞膜賦予的血液循環(huán)性能好的雙重優(yōu)勢的納米系統(tǒng),顯著延長了金納米籠的體內循環(huán)時間以及腫瘤富集量、改善了其體內腫瘤治療療效。(2)如何有效地清除腫瘤細胞但無需使用超過皮膚承受最大安全劑量的激光光照功率,是腫瘤光熱治療面臨的一大挑戰(zhàn)。我們將抗菌肽(cTL)通過Au-S鍵修飾到金納米籠的表面、隨后修飾PEG作為隱身材料,構建了兼有金納米籠的光熱效應與抗菌肽(cTL)的膜破壞作用的協(xié)同納米系統(tǒng),所得納米顆粒在皮膚可承受劑量的近紅外光照下可有效地殺死輻照區(qū)域及附近非輻照區(qū)域的癌細胞、從而有效地清除腫瘤而不傷害輻照部位的皮膚組織。(3)非治死劑量的光熱處理會使幸存腫瘤細胞兼有耐熱性和耐藥性,而這也是腫瘤光熱治療需要過高光照劑量的主要誘因。我們將一種具有酸激活的破壞細胞膜完整性的仿抗菌肽高分子(aHLP)通過硼酸酯鍵修飾到光熱試劑聚多巴胺納米粒子的表面,構建了一種可被腫瘤組織內的過氧化環(huán)境與／或近紅外光照射激活釋放出aHLP的新型納米系統(tǒng),借助aHLP對細胞膜的破壞作用清除耐熱耐藥性癌細胞、消除小鼠皮下的耐熱耐藥腫瘤、并實現(xiàn)了小鼠治療后32天的100%存活率。
[Abstract]:Cancer is a serious threat to human health and life. The traditional methods of treatment, including chemotherapy and radiation therapy, due to severe side effects and the final treatment effect is limited. Gene therapy and photothermal therapy is a new approach for cancer therapy has attracted much attention in recent years, is expected to effectively remove the tumor, without harming normal human tissues, thereby improving tumor the curative effect, reduce the adverse effect of miss. However, gene therapy and photothermal therapy system has to be improved, such as gene carrier instability in vivo photothermal reagents in accumulation of tumor is low. In this paper, we: (a) the construction of gene delivery systems, the use of self crosslinking of two disulfide increase, gene carrier stability and its transfection efficiency in vivo: (two) tumor photothermal therapy, and constructed a new type of nano thermal system, so as to improve the efficiency of tumor photothermal therapy Rate. (a) in vivo stability better gene delivery system: we found that the complexes formed by containing two disulfide bonds and polyamide DNA can be cross-linked by heating in a short time, to obtain better stability under physiological conditions, delivery in serum containing conditions and experimental transfection efficiency in vivo more high gene system. On this basis, we by heating the surface complex of hyperbranched PEG in the formation of cationic polymer and the formation of DNA shell and self protection by two disulfide linked to the surface of the compound, to form a layer of protection from complex system cannot be decomposed by blood the protein, but once into the cytoplasm by glutathione degradation of stimuli responsive protective shell, controlled release of DNA, improve the efficiency of gene transfection. (two) photothermal nanoparticles tumor therapy better: Based on gold Nano cage and polydopamine this two kinds of Pt nanoparticles, we constructed 3 different tumor photothermal therapy system, in order to improve the efficiency of treatment. (1) gold cage is a kind of near infrared photothermal conversion of nano particles, but the short circulation time limits the in vivo therapeutic effect. We the red blood cell membrane of the natural camouflage material wrapped in gold cage surface, constructed both shape of gold nanocages, nano system has dual advantages of red blood cell membrane gives blood circulation good performance, significantly prolong the circulation time of gold nanocages and tumor accumulation, improve the body the efficacy of cancer treatment. (2) but without the use of laser over skin subjected to the maximum safe dose of light power to effectively remove the tumor cells, is a great challenge to tumor photothermal therapy. We will antimicrobial peptides (cTL) through the Au-S key repair Decoration to the surface of the nano gold cage, then modified PEG as stealth materials, construction and photothermal effect with gold nano antibacterial peptide cage (cTL) and nanometer membrane system damage, the near infrared nanoparticles in the skin can withstand the dose of irradiation can effectively kill the radiation region and near the non irradiated area the cancer cells, so as to effectively remove the tumor without damaging the skin tissue irradiated. (3) will deal with non thermal death dose to tumor cell survival has heat resistance and resistance, which is also the tumor photothermal therapy need high light dose of the main incentives. We will have a complete destruction of cell membrane the imitation of acid activated antibacterial peptide polymer (aHLP) surface modified by borate ester bonding to the photothermal reagent polydopamine nanoparticles, established a kind of be peroxided environment and / or near infrared light in tumor tissue Irradiation activated the new nanoscale system that released aHLP. With the destruction of cell membrane, aHLP eliminated the heat resistant cancer cells and eliminated the heat resistant tumors in mice, and achieved 100% survival rate on the 32 day after treatment.

【學位授予單位】：中國科學技術大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R730.5;TB383.1

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