还原响应型聚合物纳米材料的制备及释药性能研究

发布时间：2018-08-03 15:37

【摘要】：聚合物纳米材料可以通过调节聚合物的组成和聚集态的形成条件达到作为药物载体的目的。当其作为药物载体时,可以装载药物分子保护其在到达组织之前不被外界环境所破坏。载药聚合物中所含双硫键在肿瘤细胞中高谷胱甘肽(GSH)下能被还原成硫醇,实现药物的定点释放。本论文以生物相容性良好的聚乙二醇为原料,设计合成还原型HNTs-聚合物纳米材料载药体系。同时以双键聚乙二醇为原料设计合成基于双硫键的还原型核交联胶束载药体系。具体工作如下:⑴设计合成还原型HNTs-PAA-MPEG纳米材料载药体系采用原子转移自由基聚合反应(ATRP),合成了两亲性嵌段聚合物MPEG-b-PtBA,酸解得到末端带羧基的嵌段聚合物MPEG-PAA。HNTs表面经过共价修饰,引入双硫键。末端带氨基的纳米管和末端带羧基的聚合物MPEG-PAA经过溶液中的静电结合得到含双硫键的还原型HNTs-PAA-MPEG纳米材料。通过核磁、凝胶渗透色谱对聚合物结构和分子量及分子量分布进行表征,证明成功合成了单分散性两亲聚合物。通过红外、扫描电镜和热重分析表明,聚合物成功接枝到HNTs表面,并且聚合物所含羧基量越多,接枝到HNTs表面的聚合物量越多。通过包载和释放阿霉素研究了HNTs-PAA-MPEG纳米材料的载药和药物释放行为。结果表明,在还原性GSH存在下,HNTs-PAA-MPEG纳米材料能够较快的释放出药物。因此,含双硫键的HNTs-PAA-MPEG纳米材料有望作为一种还原型药物载体。⑵设计合成基于双硫键的还原型核交联胶束载药体系通过自由基聚合,调控三个单体的加入量,形成侧链以聚乙二醇甲基丙烯酸酯作为亲水链段、乙酸-N-琥珀酰亚胺酯作为交联链段、MA6-Chol作为疏水链段的不同比例不同分子量的聚合物(MPEG-NSA-Chol)。用核磁和凝胶渗透色谱对聚合物结构和分子量及分子量分布进行表征,证明成功合成了不同比例不同分子量的聚合物。随后通过胱胺和乙酸-N-琥珀酰亚胺酯反应得到交联的聚合物。同时,利用荧光光谱仪、动态光散射仪和透射电镜对聚合物水溶液自组装行为进行研究。结果表明:交联后的聚合物胶束结构更稳定,尺寸更小(10-30 nm)。此外与聚合物载药胶束相对比,交联载药胶束在还原性GSH存在下,能够更快的释放出药物。因此,这种基于双硫键的还原型核交联胶束也很有潜质成为一种稳定的还原型药物载体。
[Abstract]:Polymer nanomaterials can be used as drug carriers by adjusting the composition of polymers and the formation conditions of aggregation states. When it is used as a drug carrier, it can be loaded with drug molecules to protect it from environmental damage before reaching the tissue. The disulfide bond contained in the drug-loaded polymer can be reduced to mercaptan under glutathione (GSH) in tumor cells to realize the targeted release of the drug. In this paper, a novel drug delivery system of reduced HNTs- polymer nanomaterials was designed and synthesized from polyethylene glycol (PEG) with good biocompatibility. At the same time, double bond polyethylene glycol was used as raw material to design and synthesize reductive nuclear crosslinked micelle drug loading system based on disulfide bond. The main work is as follows: 1. The drug loading system of reduced HNTs-PAA-MPEG nanomaterials was designed and synthesized. The amphiphilic block polymer MPEG-b-PtBA was synthesized by atom transfer radical polymerization (ATRP),). The surface of block polymer MPEG-PAA.HNTs with carboxyl group at the end was covalently modified by acidolysis. The disulfide bond is introduced. The reduced HNTs-PAA-MPEG nanomaterials containing disulfide bonds were obtained by electrostatic binding of terminal amino nanotubes and carboxyl group polymer MPEG-PAA. The structure, molecular weight and molecular weight distribution of the polymer were characterized by NMR and gel permeation chromatography. It was proved that the monodisperse amphiphilic polymer was successfully synthesized. Infrared scanning electron microscopy and thermogravimetric analysis showed that the polymer was grafted onto the surface of HNTs and the more carboxyl group the polymer was grafted to the surface of HNTs the more the polymer was grafted to the surface of HNTs. Drug loading and drug release behavior of HNTs-PAA-MPEG nanomaterials were studied by encapsulating and releasing adriamycin. The results showed that HNTs-PAA-MPEG nanoparticles could release drugs rapidly in the presence of reductive GSH. Therefore, HNTs-PAA-MPEG nanomaterials with disulfide bonds are expected to be used as a reductive drug carrier .2 to design and synthesize reductive nuclear cross-linked micelle drug carrier system based on disulfide bond. The amount of three monomers can be regulated by free radical polymerization. The side chain was formed with poly (ethylene glycol) methacrylate as hydrophilic segment and acetic acid-N-succinimide as crosslinking segment MA6-Chol as hydrophobic polymer (MPEG-NSA-Chol). The structure, molecular weight and molecular weight distribution of polymers were characterized by NMR and gel permeation chromatography. The crosslinked polymer was obtained by the reaction of cysteamine with acetic acid-N-succinimide ester. At the same time, the self-assembly behavior of polymer aqueous solution was studied by fluorescence spectrometer, dynamic light scattering instrument and transmission electron microscope. The results show that the crosslinked polymer micelles have more stable structure and smaller size (10-30 nm). In addition, in the presence of reductive GSH, the cross-linked drug carrier micelles can release the drug more quickly than the polymer loaded micelles. Therefore, the reduced nuclear crosslinked micelles based on disulfide bond have the potential to become a stable drug carrier.
【学位授予单位】：河南师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TB383.1;TQ460.1

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