具有pH响应及细胞核靶向功能的聚合物胶束在癌症治疗中的研究
[Abstract]:In recent years, the use of nano-carrier targeted cancer therapy, cancer treatment research has received extensive attention. In order to improve the anticancer effect of chemotherapeutic drugs and reduce the toxicity and side effects of chemotherapeutic drugs, it is particularly important to increase the uptake of nanoparticles by tumor cells and to achieve nuclear drug delivery. It is considered that the modification of the stimulation-responsive nano-carrier by cell penetrating peptide (CPP) can not only achieve the goal of tumor targeting, but also promote tumor cells to absorb a large number of nanoparticles, thus effectively inhibit the growth and reproduction of cancer cells. In chapter 2, we successfully synthesized pH responsive polymer DA-Tat-PEG-PCL (DA-Tat-PECL) with cellular penetrating peptide and nuclear localization signal modified by Tat. In order to improve the hydrophobicity of 10-hydroxycamptothecin (HCPT), increase the drug loading capacity (LC) and drug loading efficiency (EE), we grafted HCPT onto methoxy polyethylene glycol (mPEG) and synthesized the modified drug mPEG-HCPT. successfully. The structure of copolymers was verified by 1H NMR), gel permeation chromatography (FT-IR) and high performance liquid chromatography (HPLC). A micelle PECL/DA-Tat-M, with nuclear targeting and pH responsiveness was prepared by solvent volatilization. The micelle has a low critical micelle concentration, (CMC), has good thermodynamic stability and has a core-shell structure. Can effectively package hydrophobic drugs. The results of DLS and TEM show that the micelle is homogeneous spherical and its particle size is about 80nm. The drug release rate of micelles coated with mPEG-HCPT was faster than that of micelles coated with HCPT in vitro, and the LC and EE of micelles were more than 5% and 70%, respectively. The pH response of the micelles showed that under pH 6.8, the amide-bond between (DA) and Tat broke rapidly, and Tat was completely exposed, which caused the micelle to reverse the charge and the surface charge changed from negative to positive. The particle size also increased to about 90 nm. In chapter 3, a series of biological evaluation of the charge reversal micelle PECL/DA-Tat-M in vitro was carried out. The results showed that the blank micelles of PECL/DA-Tat-blank M had good biocompatibility and could inhibit tumor cells after loading mPEG-HCPT. And has the lowest IC50 value in pH6.8. We found that the uptake and subcellular localization of the micelles by tumor cells were affected by pH. At pH 6.8, the micelles were ingested in large quantities by tumor cells and could be effectively enriched around the nucleus after entering the cells. The results showed that DA shedded from the copolymer and Tat was exposed, which promoted the endocytosis of the cells. After entering the cells, Tat played the role of nuclear localization. The micelles can achieve nuclear targeting function. In chapter 4, an in situ model and an ectopic model of breast cancer in 4T1 mice were established to verify the antitumor effect of the micelle in vivo. The results showed that compared with control group, blank micelle group, HCPT group and mPEG-HCPT combined PECL-M micelle group, PECL/DA-Tat-M micelles could not only significantly inhibit tumor growth, but also concentrate on tumor tissue and avoid systemic side effects. The survival rate of experimental animals was improved and the safety was higher. The results of TUNEL staining showed that the micelle group had the highest apoptosis rate and the best tumor inhibition effect. The results of spontaneous lung metastasis in situ model also showed that PECL/DA-Tat-M micelles inhibited lung metastasis, and the lung HE staining showed that the alveolar structure of the group was normal and no pulmonary metastasis occurred. It is further demonstrated that this charge reversal micelle effectively inhibits spontaneous lung metastasis.
【学位授予单位】:西南交通大学
【学位级别】:硕士
【学位授予年份】:2017
【分类号】:R730.5
【相似文献】
相关期刊论文 前10条
1 税庆华;苏淮;李津;蓝伟伟;武利芬;;pH对酒石酸溴莫尼定滴眼液稳定性的影响[J];药学实践杂志;2008年05期
2 李玲,付美兰,韩璐;以急性淋巴细胞白血病起始的Ph′阳性慢性粒细胞白血病1例[J];临床血液学杂志;1995年01期
3 时薛丽,崔红,张露野,孙轶杰;0.2%甲硝唑葡萄糖注射液灭菌后PH值的变化[J];牡丹江医学院学报;1995年03期
4 谢殿左;闫文生;张永宏;韩伟英;吴志军;王莉;;影响莪术油葡萄糖注射液PH值的因素[J];黑龙江医药;1996年02期
5 卢远清,董家蔷,李晓云,王来慈,陈学新;Ph(+)嗜酸粒细胞白血病1例[J];白血病;1997年02期
6 孙葳;陆大祥;丁勇;李楚杰;;不同pH及封闭氨基端对甘氨酸拮抗内毒素作用的影响[J];中国病理生理杂志;1997年02期
7 M.Schrappe;M.Aricò;J.Harbott;A.Biondi;M.Zimmermann;V.Conter;A.Reiter;M.G.Valsecchi;H.Gadner;G.Basso;C.R.Bartram;F.Lampert;H.Riehm;G.Maserat;肖昕;;Ph~+儿童急性淋巴细胞性白血病:良好的类固醇初始反应可以早期预测较件的治疗结果[J];德国医学;2000年01期
8 常春康;Ph阳性急性淋巴细胞白血病若干问题研究进展[J];白血病.淋巴瘤;2001年04期
9 朱玉兰,周晓,刘惠萍;两种方法配制甲硝唑葡萄糖注射液的稳定性比较[J];华西药学杂志;2002年05期
10 张聪恪,刘征,廖兴广,张秀丽,张蒙,汪世山;pH与低水活度对单核细胞增生李斯特菌生长的影响[J];中国卫生检验杂志;2003年03期
相关会议论文 前10条
1 王亮;朱康儿;查显丰;陈少华;杨力建;陈思;李扬秋;;一例Ph阳性慢性髓细胞白血病患者发生Ph阴性急性淋巴细胞白血病变前后外周血T细胞克隆性的演变[A];第12届全国实验血液学会议论文摘要[C];2009年
2 崔颜;苏宝法;任斌;田中群;;基于表面增强拉曼光谱技术的细胞内pH传感研究[A];第十五届全国光散射学术会议论文摘要集[C];2009年
3 章艳茹;王婷玉;邹德慧;隋伟薇;李增军;徐燕;付明伟;赵耀中;齐军元;王建祥;秘营昌;邱录贵;;成人Ph阳性急性淋巴细胞白血病疗效分析[A];2012中国器官移植大会论文汇编[C];2012年
4 张U,
本文编号:2370105
本文链接:https://www.wllwen.com/yixuelunwen/zlx/2370105.html