HA-QDs-MEL的合成与评价

发布时间：2018-07-04 23:53

本文选题：透明质酸 + 量子点　；参考：《武汉理工大学》2014年硕士论文

【摘要】：本文成功制备了一种具有智能示踪，受体介导靶向性的美法仑（MEL）前药透明质酸（HA）-量子点（QDs）-美法仑（HA-QDs-MEL）。该给药系统是将具有细胞毒性的美法仑药物选择性导向至特定的肿瘤细胞（卵巢癌、乳腺癌等），使药物在肿瘤细胞部位释放并达到较高的药物浓度，在提高药物生物利用度的同时增加了药物对肿瘤的选择杀伤性，因此本给药系统可以很好地解决化疗药物普遍存在毒副作用大、不良反应严重等问题，并可以对药物的运转进行示踪研发。本文进行了HA-QDs-MEL给药系统的合成。采用水热法制备了CdTe/CdS量子点。并用L-半胱氨酸对量子点的表面官能团化。制备了L-半胱氨酸修饰的CdTe/CdS量子点。其次制备了透明质酸与L-Cys-CdTe/CdS量子点交联反应产物，作为美法仑药物的载体。利用透明质酸上的羧基和量子点上的氨基进行酰胺缩合。对各步骤实验产物进行傅里叶红外和核磁氢谱等表征，结果证明合成成功。再次，以HA-QDs作为载体，通过酰胺缩合反应制备得到HA-QDs-MEL。利用所合成的载体HA-QDs和药物美法仑苄酯，美法仑苄酯在酸性条件下水解后，得到最终合成产物HA-QDs-MEL。利用HA-QDs上部分空位游离的羧基，用1-乙基-3-（3-二甲基氨基丙基）-碳化二亚胺(EDC)活化羧基，并且在NHS作用下与美法仑苄酯上游离的氨基缩合生成酰胺键连接的HA-QDs-MEL酯，然后在酸性条件下水解得到产物HA-QDs-MEL。对HA-QDs-MEL进行红外核磁等表征，结果证明成功载药美法仑，对HA-QDs-MEL进行粒径分析，，粒径均一分散，在200到500nm左右。本文再对所制备的的HA-QDs-MEL给药系统的药物释放，HA-QDs-MEL的释放有一定的pH选择性，在模拟肿瘤细胞酸性条件下释放较好，并且同时具有一定的缓释作用，释药的曲线较平缓，说明有缓释作用并且，证明该载药系统有缓控释并且具有pH敏感性。本文还对载药系统进行了细胞评价，对其进行毒性试验，摄取试验，定位实验和受体竞争抑制实验。结果表明HA-QDs-MEL的毒性有极大的改善，减少其对正常细胞的杀伤力。药物内吞到溶酶体，由溶酶体传递至细胞核，从而杀死肿瘤细胞。由HA受体竞争抑制性实验表明，HA受体对HA-QDs-MEL有抑制作用，说明CD44受体对给药系统有靶向作用。
[Abstract]:In this paper, an intelligent tracer and receptor-mediated targeting meflon (Mel) prodrug hyaluronic acid (HA) -quantum dot (QDs) -mefacalen (HA-QDs-MEL) has been successfully prepared. The drug delivery system is to selectively target cytotoxic mefalen drugs to specific tumor cells (ovarian cancer, breast cancer, etc.), allowing the drug to be released at tumor cell sites and reach higher drug concentrations. In addition to increasing the bioavailability of drugs, it also increases the choice of drugs for tumor killing. Therefore, this drug delivery system can solve the common problems of large side effects and serious adverse reactions of chemotherapeutic drugs. And can carry on the tracer research and development to the operation of the drug. The HA-QDs-MEL drug delivery system was synthesized. CdTe / CDs quantum dots were prepared by hydrothermal method. The surface functionalization of quantum dots with L-cysteine was investigated. L- cysteine modified CdTe / CDs quantum dots were prepared. Secondly, the crosslinking products of hyaluronic acid and L-Cys-CdTe-CdS quantum dots were prepared, which were used as the carrier of mefalen. Amides were condensed from carboxyl groups on hyaluronic acid and amino groups on quantum dots. The products were characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic hydrogen spectroscopy (NMR). The results show that the synthesis is successful. Thirdly, using HA-QDs as carrier, HA-QDs-MEL was prepared by amide condensation reaction. The final product HA-QDs-MELL was obtained by hydrolysis of the synthesized carrier HA-QDs and the drug mefallen benzyl ester under acidic conditions. Using partially vacant carboxyl groups on HA-QDs, 1-ethyl-3- (3-dimethyl aminopropyl) -carbodiimide (EDC) was used to activate carboxyl groups and to form amide-bonded HA-QDs-MEL esters by condensation of amphalentyl esters with free amino groups under the action of NHS. The product HA-QDs-MEL was obtained by hydrolysis under acidic conditions. The HA-QDs-MEL was characterized by IR NMR. The results showed that the drug was successfully loaded with mefacalen. The particle size of HA-QDs-MEL was analyzed and the particle size was uniformly dispersed, ranging from 200 to 500nm. In this paper, the release of HA-QDs-MEL from HA-QDs-MEL delivery system was pH selective, and the release of HA-QDs-MEL was better under the simulated acidic condition of tumor cells. At the same time, the release curve of HA-QDs-MEL was smooth, and the release curve of HA-QDs-MEL was smooth. The results show that the drug delivery system has slow and controlled release and pH sensitivity. The cytotoxicity, uptake, localization and competitive inhibition of the drug delivery system were evaluated. The results showed that the toxicity of HA-QDs-MEL was greatly improved and the cytotoxicity of HA-QDs-MEL to normal cells was reduced. Drugs endocytosis to lysosomes, from lysosomes to the nucleus, killing tumor cells. The competitive inhibition of HA receptor showed that HA-QDs-MEL was inhibited by HA-QDs-MEL, indicating that CD44 receptor could target the drug delivery system.
【学位授予单位】：武汉理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

【参考文献】