pH和还原双响应交联聚乙二醇-葡聚糖纳米粒子用作细胞内药物传输系统

发布时间：2018-03-24 19:50

本文选题：药物传输　切入点：纳米粒子　出处：《长春工业大学》2017年硕士论文

【摘要】：在过去的几十年里,已经研发了许多种环境敏感的聚合物纳米粒子(NPs)用作肿瘤靶向传输抗肿瘤药物的智能纳米载体。临床和预临床研究已经表明,聚合物纳米载体能够延长体内的循环时间,通过增强渗透和滞留(EPR)效应特定靶向到肿瘤组织,并减少药物的毒副作用,从而提高治疗效率。由于与正常组织相比,肿瘤细胞具有特定的肿瘤微环境,所设计的纳米载体通常能够在血液循环中稳定存在,一旦在肿瘤部位或细胞内空间遇到生物刺激,便能响应性地释放所担载物。在这些情况下,人们广泛研究了各种响应性刺激,如pH,谷胱甘肽(GSH),温度,光和酶。为了研发应用于药物传输系统的刺激敏感性材料,已经将多种功能和刺激响应部分与具有良好生物相容性及生物降解性的不同聚合物相结合。葡聚糖是亲水性多糖,已经广泛应用于构建纳米粒子药物传输系统。抗肿瘤药物可以直接键合到葡聚糖的骨架上,也可以包载到葡聚糖构建的疏水核胶束中,用于全身药物传输系统。然而,很少有关于核交联葡聚糖用于抗肿瘤传输系统的报道。pH和还原双重敏感的纳米粒子广泛应用于刺激响应药物载体,用来改善抗癌药物在细胞内的传输。如何在提高载药效率的同时降低毒副作用,如何实现药物在正常生理条件下少量释放,同时在细胞内条件下快速释放等仍是需要解决的问题。本文通过简单的化学交联方法制备了一种聚乙二醇接枝葡聚糖纳米粒子(CPD NPs),用于pH与还原双响应药物传输体系。所得到的CPD纳米粒子是均匀的球形结构,粒径大小在69 nm至107 nm之间。随后将抗肿瘤药物阿霉素高效担载到CPD纳米粒子中,通过体外释放实验,说明该载药体系具有还原及pH双重响应性。流式细胞术和共聚焦显微镜结果证明载阿霉素的CPD纳米粒子可以有效的进入到细胞内,并且能够在细胞微环境中成功释放阿霉素。另外,细胞毒性实验显示,CPD纳米粒子对于正常细胞以及肿瘤细胞均具有很好的生物相容性,而且载阿霉素的CPD纳米粒子能够明显抑制多种肿瘤细胞的细胞增殖。因此,在肿瘤的临床治疗中,该种生物相容的CPD纳米粒子拥有巨大潜力应用于细胞内药物传输系统。
[Abstract]:In the past few decades, many kinds of environment-sensitive polymer nanoparticles (NPs) have been developed as intelligent nano-carriers for tumor targeted delivery of anti-tumor drugs. Clinical and pre-clinical studies have shown that. Polymer nanocarriers can prolong the circulation time in vivo, target tumor tissues by enhancing the effect of osmotic and retention EPRs, and reduce the toxic and side effects of drugs, thus improving the therapeutic efficiency. Tumor cells have a specific tumor microenvironment, and the designed nano-carriers usually exist stably in the blood circulation, once the biological stimulation is encountered in the tumor site or in the cell space. In these cases, a wide range of responsive stimuli, such as pH, glutathione glutathione GSH, temperature, light and enzymes, have been studied in order to develop stimulus-sensitive materials for use in drug delivery systems. Multiple functions and stimuli have been combined with different polymers with good biocompatibility and biodegradability. Dextran is a hydrophilic polysaccharide. Antitumor drugs can be directly bonded to the skeleton of dextran or encapsulated into the hydrophobic nuclear micelles constructed by dextran for use in a systemic drug delivery system. Few reports on the use of nuclear crosslinked dextran in antitumor transport systems. Ph and reductive dual sensitive nanoparticles have been widely used in stimulus-responsive drug carriers. To improve the delivery of anticancer drugs in cells. How to improve the efficiency of drug delivery while reducing side effects, how to achieve a small amount of drug release under normal physiological conditions, At the same time, rapid release in intracellular condition is still a problem to be solved. In this paper, a kind of polyethylene glycol grafted dextran nanoparticles (CPD NPsN) was prepared by simple chemical crosslinking method, which was used for pH and reduction double response drug transport. System. The obtained CPD nanoparticles are spherical in structure. The particle size ranged from 69 nm to 107 nm. The antitumor drug doxorubicin was then loaded into CPD nanoparticles and released in vitro. The results of flow cytometry and confocal microscopy showed that the CPD nanoparticles loaded with doxorubicin could effectively enter the cells. In addition, cytotoxicity tests show that CPD nanoparticles have good biocompatibility for both normal cells and tumor cells. Moreover, CPD nanoparticles loaded with adriamycin can significantly inhibit the proliferation of various tumor cells. Therefore, the biocompatible CPD nanoparticles have great potential to be used in intracellular drug delivery systems in the clinical treatment of tumors.
【学位授予单位】：长春工业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1;TB383.1

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