纳米医药：基因递送与肿瘤光热治疗

发布时间：2018-03-28 01:17

本文选题：二硫键　切入点：自交联　出处：《中国科学技术大学》2016年博士论文

【摘要】：肿瘤严重威胁着人类的健康甚至生命。传统治疗方法,主要包括化学疗法和放射疗法,由于副作用严重而最终治疗效果有限。基因治疗与光热治疗是近年来备受关注的新型肿瘤治疗方式,有望有效清除肿瘤、同时又不伤害人体正常组织,从而改善肿瘤治疗疗效、降低脱靶毒副作用。但是,基因治疗与光热治疗系统还待改善,比如基因载体在体内不稳定、光热试剂在肿瘤的富集量较低等。在本论文中,我们在：(一)基因递送系统的构建方面,利用二硫键的自交联,增加基因载体的稳定性以及其在体内的转染效率：(二)肿瘤光热治疗方面,构建了新型光热纳米系统,从而改善了肿瘤光热治疗效率。(一)体内稳定性更好的基因递送系统：我们发现利用含有二硫键的聚酰胺键和DNA形成的复合物可以通过加热在短时间之内使其交联,获得了在生理条件下稳定性更好、在含血清条件下和实验小鼠体内转染效率都更高的基因递送系统。在此基础上,我们通过加热使超支化PEG在阳离子聚合物与DNA形成的复合物的表面形成保护壳层并通过二硫键的自交联使其稳定在复合物的表面,以形成一层可保护所得复合物系统不被血液中的蛋白所分解、但一旦进入细胞质可被谷胱甘肽降解的刺激响应性保护壳,实现DNA的可控释放、提高基因转染效率。(二)肿瘤治疗更好的光热纳米颗粒：基于金纳米笼和聚多巴胺这两种光热纳米颗粒,我们构建了3种不同的肿瘤光热治疗系统,以期改善治疗效率。(1)金纳米笼是一种近红外光热转换纳米颗粒,但其较短的体内循环时间限制了其在体内治疗疗效。我们将血红细胞膜这种天然隐身材料包裹在金纳米笼表面,构建了既有金纳米笼的形貌、又有血红细胞膜赋予的血液循环性能好的双重优势的纳米系统,显著延长了金纳米笼的体内循环时间以及肿瘤富集量、改善了其体内肿瘤治疗疗效。(2)如何有效地清除肿瘤细胞但无需使用超过皮肤承受最大安全剂量的激光光照功率,是肿瘤光热治疗面临的一大挑战。我们将抗菌肽(cTL)通过Au-S键修饰到金纳米笼的表面、随后修饰PEG作为隐身材料,构建了兼有金纳米笼的光热效应与抗菌肽(cTL)的膜破坏作用的协同纳米系统,所得纳米颗粒在皮肤可承受剂量的近红外光照下可有效地杀死辐照区域及附近非辐照区域的癌细胞、从而有效地清除肿瘤而不伤害辐照部位的皮肤组织。(3)非治死剂量的光热处理会使幸存肿瘤细胞兼有耐热性和耐药性,而这也是肿瘤光热治疗需要过高光照剂量的主要诱因。我们将一种具有酸激活的破坏细胞膜完整性的仿抗菌肽高分子(aHLP)通过硼酸酯键修饰到光热试剂聚多巴胺纳米粒子的表面,构建了一种可被肿瘤组织内的过氧化环境与／或近红外光照射激活释放出aHLP的新型纳米系统,借助aHLP对细胞膜的破坏作用清除耐热耐药性癌细胞、消除小鼠皮下的耐热耐药肿瘤、并实现了小鼠治疗后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.

【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5;TB383.1

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