聚乙二醇修饰的刺激响应性纳米水凝胶的制备及其药物控释研究

发布时间：2018-05-07 17:41

本文选题：药物传送系统 + 纳米水凝胶　；参考：《兰州大学》2016年硕士论文

【摘要】：长期以来,科研工作者一直致力于研究和发展生物相容且生物可降解的刺激响应性药物传送系统,以期实现药物在病变位点的主动或被动靶向传送和释放,从而减少药物的毒副作用、改善药物在人体内的生物分布以及疾病治疗效果。纳米水凝胶凭借自身的诸多优点在药物运输系统应用方面表现出了巨大的潜力,受到了越来越多的关注。纳米水凝胶的生物相容性十分良好,较大的比表面积可进行多元化修饰和生物接合,复杂的内部网络有助于药物分子的负载,亲水性表面以及稳定的交联结构可增加纳米水凝胶的体内循环时间。合成类纳米水凝胶的较慢的生物可降解性和较低的生物相容性是其用作药物载体的主要阻碍因素,生物相容的天然多糖材料则存在着载药效率低和体内降解性能欠佳等缺陷。本论文针对上述问题分别以合成类甲基丙烯酸(MAA)和天然类海藻酸钠(SA)为主要原料,并采用生物相容性良好的聚乙二醇(PEG)分子进行修饰,通过不同的合成方法制备了载药性能优良、生物相容且生物可降解的单重或双重刺激响应性纳米水凝胶。采用红外光谱(FTIR)进行结构的表征,通过透射电镜(TEM)和动态光散射(DLS)考察形貌和粒径,通过四甲基偶氮唑盐微量酶反应比色法(MTT)考察载体的细胞相容性,并进行了抗癌药物阿霉素(DOX)的负载和控制释放方面的研究。本学位论文的研究工作及取得的主要成果包括以下三个方面:1.采用蒸馏沉淀一步法,以MAA和聚乙二醇单甲醚甲基丙烯酸酯(PEGMA)为单体、N,N'-双(丙稀酰)胱胺(BACy)为交联剂,在AIBN的引发下,制备了生物相容且可体内降解的纳米水凝胶(PMPB)。采用FTIR表征了不同交联度PMPB纳米水凝胶的结构,重点研究了高交联度纳米水凝胶的刺激响应性药物释放行为。通过TEM考察了该纳米水凝胶的体外降解行为,实验表明该PMPB纳米水凝胶微球在10 mM GSH或DTT作用下基本全部发生降解,降解成了透射电镜下基本不可见的线型聚合物链。PMPB纳米水凝胶的阿霉素负载效率可高达95%以上。后续的释放实验表明,PMPB纳米水凝胶具有十分明显的pH和氧化还原响应性。最后,选择MTT法评估了PMPB纳米水凝胶的细胞相容性,实验结果表明PMPB纳米水凝胶具有良好的细胞相容性。2.采用碳二亚胺(EDCI)催化的均相胱胺交联法制备接枝有PEG的氧化海藻酸钠纳米水凝胶(OSA-mPEG),该类天然多糖型纳米水凝胶与合成类水凝胶相比显示出了生物相容性良好等突出优点。在TEM观察下,较高氧化度OSA-mPEG纳米水凝胶(DO%=20%)的形貌较为规整,平均粒径约为45 nm。DLS测试结果表明该纳米水凝胶的单分散性良好,负载DOX后其粒径缩小至170nm。考察了不同溶剂配比、醋酸用量、DOX加入量对OSA-mPEG纳米水凝胶药物负载过程的影响,载体主要通过与药物DOX反应生成的席夫碱键来进行药物负载,较高氧化度纳米水凝胶具有较好负载结果,负载量和封装效率分别为22.7±0.4%和59.4±1.9%。在载药纳米水凝胶的控释实验中,较高氧化度纳米水凝胶表现出了较好的pH响应释放性能。细胞毒性和细胞摄入实验表明,较高氧化度纳米水凝胶的细胞相容性良好,负载有DOX的纳米水凝胶则对细胞显示出了一定的杀伤力且可被细胞内在化并释放DOX。3.采用简单易行的钙离子交联法分别制备了原位负载药物DOX的SA、OSA、OSA-mPEG纳米水凝胶,并将其用于DOX的负载和控释。在制备纳米水凝胶的同时完成了药物的负载,不仅简化了实验步骤,而且有利于改善药物在载体内部的分布情况。通过TEM观察该载药纳米水凝胶的形貌和粒径,发现钙交联OSA-mPEG载药纳米水凝胶的形貌为近似球形且粒径约为50 nm,经DLS测得该纳米水凝胶在水中的流体力学直径为135 nm,该尺寸的载体在体内传送过程中具有很大的优势。该天然多糖类纳米水凝胶载药量大于26%,载药效率高达90%。在不同的pH条件下,考察组成不同的钙交联纳米水凝胶的释放行为。研究发现,在释放过程中该类纳米水凝胶均显示出了一定的pH响应性。其中OSA-mPEG载药纳米水凝胶的pH响应性最为明显,pH为5.0时可持续稳定地释放DOX,释放过程可持续三天以上。
[Abstract]:For a long time, researchers have been working on the research and development of biocompatible and biodegradable stimulative responsive drug delivery systems, in order to realize the active or passive targeting and release of drugs at the lesion sites, thus reducing the toxic and side effects of drugs, improving the biological distribution of drugs in the human body and the effect of disease treatment. Mica hydrogel has shown great potential in the application of drug transport system with its many advantages. It has attracted more and more attention. The biocompatibility of nano hydrogels is very good, the larger specific surface area can be diversified and bioconjugation. Complex internal networks help the load and hydrophilicity of drug molecules. The surface and stable cross-linking structure can increase the cycle time in vivo. The slow biodegradability and low biocompatibility of the synthetic nanosels are the main impediments to use as drug carriers. The biocompatible natural polysaccharide materials have low drug loading efficiency and poor biodegradability in the body. In this paper, the main materials of this thesis are synthetic methacrylic acid (MAA) and natural sodium alginate (SA), and a good biocompatible polyethylene glycol (PEG) molecule is used to modify. The single or dual stimulus response of biocompatible and biodegradable materials is prepared by different synthetic methods. The structure was characterized by infrared spectroscopy (FTIR). The morphology and particle size were investigated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The cell compatibility of the carrier was investigated by four methyl azazolazolium salt Microenzyme reaction Colorimetry (MTT), and the load and control release of the anticancer drug adriamycin (DOX) were studied. The research work and the main achievements of this dissertation include the following three aspects: 1. using MAA and polyethylene glycol monomethyl ether methacrylate (PEGMA) as monomers, N, N'- double (BACy) as crosslinker, and the preparation of biocompatible and biodegradable nano hydrogel (PMP) by AIBN B). The structure of PMPB nano hydrogels with different crosslinking degrees was characterized by FTIR. The response of the nano hydrogels with high crosslinking degree was studied. The degradation behavior of the nano hydrogel was investigated by TEM. The experiment showed that the PMPB nanosels were degraded and degraded under the action of 10 mM GSH or DTT. The adriamycin load efficiency of the.PMPB nano hydrogel which was basically invisible under transmission electron microscopy could be as high as 95%. The subsequent release experiments showed that the PMPB nano hydrogel had very obvious pH and redox responsiveness. Finally, the cell compatibility of the PMPB nano hydrogel was evaluated by the MTT method, and the experimental result table was evaluated. The bright PMPB nano hydrogel has good cytocompatibility.2. using carbon two imide (EDCI) catalyzed homogeneous cystamine crosslinking method to prepare PEG oxidized sodium alginate nano hydrogel (OSA-mPEG). This kind of natural polysaccharide nano hydrogel shows good biocompatibility and other outstanding advantages compared with synthetic hydrogel. In TEM observation The morphology of the high oxidation degree OSA-mPEG nano hydrogel (DO%=20%) was relatively regular. The average particle size was about 45 nm.DLS showed that the mono dispersibility of the nano hydrogel was good. After the load DOX, the particle size of the gel was reduced to 170nm., and the proportion of solvent, the amount of acetic acid and the amount of DOX added to the drug loading process of the OSA-mPEG nano hydrogel were investigated. The carrier is loaded mainly through the Schiff base bond generated by the drug DOX reaction. The high oxidation degree nano hydrogel has a good load result, the load and the encapsulation efficiency are 22.7 + 0.4% and 59.4 + 1.9%. respectively in the controlled release experiment of the nano hydrogel. The higher oxygen degree nano hydrogel shows a better pH response. The cytotoxicity and cell intake experiments showed that the high oxidation degree of the nano hydrogel had good cytocompatibility, and the nano hydrogel loaded with DOX showed a certain killing force and could be internalized by the cell and released the DOX.3. by the simple and easy calcium crosslinking method to prepare the SA of the in situ loaded drug DOX respectively. OSA, OSA-mPEG nanosels were used for the load and controlled release of DOX. The loading of the nano hydrogels was completed while preparing the nano hydrogel, which not only simplified the experimental procedure, but also improved the distribution of the drug in the carrier. The morphology and particle size of the nano hydrogel were observed by TEM, and the calcium crosslinked OSA-mPEG drug was found. The morphology of the nano hydrogel is approximately spherical and the particle size is about 50 nm, and the hydrogel diameter of the nano hydrogel is 135 nm in water by DLS. The size of the carrier has a great advantage in the transmission process in the body. The natural polysaccharide nano hydrogel contains more than 26%, and the drug loading efficiency is up to 90%. under the different pH conditions. The release behavior of different calcium crosslinked nanosels was formed. It was found that the nano hydrogels showed a certain pH responsiveness during the release process, of which the pH responsiveness of the OSA-mPEG nanoparticles was the most obvious, and the DOX was released steadily and steadily when pH was 5, and the release process lasted for more than three days.

【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：TQ460.1;O648.17

【相似文献】