基于粒径的生物效应构建肿瘤微酸环境响应性药物载体及其应用

发布时间：2018-09-01 07:49

【摘要】：纳米载药系统因其独特的结构特点和理化性质在肿瘤治疗方面得到广泛的研究与应用。为了实现高效而低毒的化疗效果,许多高校、科研院所及医药企业在此方面开展了大量的研发工作。随着纳米技术和载体材料的迅猛发展,各种各样的纳米载药系统不断涌现。为了着实提高化疗药物的抗肿瘤效果,合理设计与构建纳米载体系统至关重要。为此,本论文基于机体和肿瘤生理性质,系统考察了粒径对聚合物胶束药物递送效率的影响,在此基础上设计并构建了一种肿瘤微酸环境响应性药物载体系统。本论文的主要研究内容如下：1、粒径对聚合物胶束体内外性能的影响研究。通过对聚合物投料比的控制,合成出一系列不同分子量的MPEG-PLA共聚物,制备了30、45、60、118和230 nm等不同粒径的聚合物胶束,系统考察了粒径对胶束体内外性能的影响。实验结果表明,粒径对60 nm及以下小粒径胶束体内外性能的影响不明显。这些小粒径胶束具有较强的肿瘤组织渗透能力,肿瘤部位蓄积量大,但体内循环时间短。大粒径胶束(230 nm)的稳定性稍差,药物释放速率稍快,细胞内化能力稍弱,体内循环时间短及肿瘤内穿透能力弱。相比之下,粒径118 nm的胶束具有较长的体内循环时间,但瘤内穿透能力不及小粒径胶束。粒径对胶束的体外细胞毒性的影响不明显。体内药效学结果表明,小粒径胶束能显著提高药物的抑瘤效果。2、构建了一种针对肿瘤微酸环境响应的粒径/电位可变药物递送系统,载体材料为含有聚(β-氨基酯)(PAE)链段的两亲性嵌段共聚物MPEG-PLA-PAE。采用该聚合物制备了粒径为100-200 nm的胶束,证明了具有较长的体内循环时间。在肿瘤部位的低pH环境下,由于PAE链段发生质子化作用,胶束的核壳结构发生重构,致使胶束的粒径减小和表面电荷增加,从而增强了其在肿瘤组织中的穿透能力并促进了肿瘤细胞的摄取。因此,该智能载体系统具有体内循环时间长、肿瘤内穿透能力强、肿瘤细胞摄取量高和肿瘤内蓄积量大等优势,能显著提高药物的抗肿瘤效果。采用姜黄素和多西他赛两种模型药物,以人乳腺癌MCF-7细胞和人口腔表皮样癌KB细胞分别建立两种体内外药效学评价模型,对该载体系统的体内外性能进行评价。
[Abstract]:Nano-drug delivery system has been widely studied and applied in tumor therapy because of its unique structure and physical and chemical properties. In order to achieve the effect of high efficiency and low toxicity, many universities, scientific research institutes and pharmaceutical enterprises have carried out a lot of research and development in this field. With the rapid development of nanotechnology and carrier materials, a variety of nano-drug delivery systems are emerging. In order to improve the anti-tumor effect of chemotherapeutic drugs, it is very important to design and construct nano-carrier system. Therefore, based on the physiological properties of human body and tumor, the effect of particle size on delivery efficiency of polymer micelles was systematically investigated, and a novel drug carrier system for tumor microacid environment was designed and constructed. The main contents of this thesis are as follows: 1. The effect of particle size on the properties of polymer micelles in vivo and in vitro. A series of MPEG-PLA copolymers with different molecular weights were synthesized by controlling the feed ratio of polymers. Polymer micelles with different particle sizes, such as 30O45,60118 and 230 nm, were prepared. The effects of particle size on the properties of micelles in vivo and in vitro were systematically investigated. The experimental results show that the effect of particle size on the in vivo and in vitro properties of micelles with small particle size under 60 nm is not obvious. These small micelles have strong osmotic ability of tumor tissue, large accumulation of tumor site, but short circulation time in vivo. The stability of large particle micelles (230 nm) was slightly poor, the drug release rate was faster, the ability of cell internalization was weak, the internal circulation time was short and the penetration ability of tumor was weak. In contrast, the micelles with a diameter of 118 nm had a longer circulating time in vivo, but the intratumoral penetration ability was not as good as that of the small diameter micelles. The effect of particle size on the cytotoxicity of micelles in vitro was not obvious. The results of pharmacodynamics in vivo showed that the small particle size micelles could significantly improve the inhibitory effect of the drug. A novel particle size / potential variable drug delivery system was constructed for the response of tumor microacid environment. The carrier material is amphiphilic block copolymer MPEG-PLA-PAE. containing poly (尾 -aminoester) (PAE) segment. The micelles with a particle size of 100 to 200 nm were prepared by using the polymer. It was proved that the micelles had a long circulating time in vivo. In the low pH environment of the tumor site, the core-shell structure of the micelles was reconstructed due to the protonation of the PAE segment, which resulted in the decrease of the particle size and the increase of the surface charge of the micelles. It enhances its penetrating ability in tumor tissue and promotes the uptake of tumor cells. Therefore, the intelligent carrier system has the advantages of long internal circulation time, strong penetrating ability, high uptake of tumor cells and large amount of tumor accumulation, which can significantly improve the anti-tumor effect of the drug. By using curcumin and docetaxel, two in vitro and in vivo pharmacodynamics evaluation models of human breast cancer MCF-7 cells and human oral epidermoid carcinoma KB cells were established to evaluate the in vitro and in vivo performance of the vector system.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R943

【相似文献】