单壁碳纳米管复合盐酸阿霉素脂质体给药系统的初步研究

发布时间：2018-05-18 11:10

本文选题：盐酸阿霉素 + 脂质体　；参考：《郑州大学》2014年硕士论文

【摘要】：盐酸阿霉素（Doxorubicin，DOX）作为广谱抗肿瘤药物，对各种生长周期的肿瘤细胞都有杀灭作用，但较大的心脏毒性限制了其临床应用。单壁碳纳米管(Single-walled Carbon Nanotubes，SWNTs)具有独特的药物传递和光热治疗的性质，其巨大的比表面积、大离域π键、独特的跨膜能力及在700～1,100nm范围的近红外光下高吸收产热能力，这些特性使SWNTs可成为一种新型的药物载体材料。本课题利用脂质材料同时包裹SWNTs和阿霉素，构建一种肿瘤靶向复合纳米给药体系（Lys/CNTs-DOX-Lip），以期达到化疗，光疗，热疗三者的协同作用。本课题首先利用赖氨酸（Lysine，Lys）对SWNTs进行功能性修饰，然后对Lys/CNTs-DOX-Lip复合制剂的处方和制备工艺进行了研究。通过对实验影响较大的单因素进行考察，，确定最终处方：磷脂与胆固醇质量比为5:1，药脂比为1:10，探超时间为2min，脂质体与碳管比为2:1。最终制备的复合制剂外观为黑红色溶液，且放置稳定，超滤法测定制剂包封率为85.9%，碳纳米管的最终浓度约为200μg·ml-1，阿霉素药物浓度约为1mg·ml-1。对其药剂学性质研究，测定其粒径为223±5.9nm，电位为-20±2.3mv。体外释药考察了不同的pH环境条件下对制剂释药行为的影响，表明Lys/CNTs-DOX-Lip复合制剂具有明显的缓释特性，同时具有一定的pH敏感性。本课题以SD大鼠为模型动物，采用HPLC法测定血浆中的药物浓度，研究Lys/CNTs-DOX-Lip复合制剂的体内药代动力学特征。结果表明：与DOX溶液组相比，Lys/CNTs-DOX-Lip在体内具有一定缓释作用，延长药物在体内的作用时间，提高生物利用度。本课题以S180荷瘤小鼠为模型动物，采用HPLC测定各组织中的药物浓度，研究Lys/CNTs-DOX-Lip复合制剂在荷瘤小鼠各组织的分布情况。结果表明复合制剂具有一定的肿瘤靶向性，减小了心脏毒性。本课题同时考察了Lys/CNTs-DOX-Lip复合制剂及DOX对照液对S180荷瘤小鼠生命质量的影响，以相对肿瘤体积、体重、存活率、饮水量、饮食量等为评价指标；通过在剂量范围内给药的小鼠的心，肝，脾，肺，肾，脑，瘤等主要组织的HE染色分析，考察给药系统对小鼠的主要脏器的毒性。结果表明，Lys/CNTs-DOX-Lip制剂组表现出良好的抗肿瘤效果，且对小鼠的体质量，日饮水饮食量未产生影响，精神状态良好，生活质量得到提高。HE染色结果表明，Lys/CNTs-DOX-Lip对小鼠的主要脏器在剂量范围内没有产生明显的毒性。
[Abstract]:As a broad-spectrum antitumor drug, doxorubicin hydrochloride (Doxorubicindox) can kill tumor cells in various growth cycles, but its clinical application is limited by its large cardiac toxicity. Single-walled Carbon nanotubes (SWNTs) have unique properties of drug delivery and photothermal therapy, their large specific surface area, large delocalized 蟺 bonds, unique transmembrane ability and high absorption of heat under near-infrared light in the range of 700~1100nm. These properties make SWNTs a new drug carrier material. In order to achieve the synergistic effects of chemotherapy, phototherapy and hyperthermia, a tumor targeting compound nano-drug delivery system, Lys-CNTs-DOX-Lipan, was constructed by encapsulating SWNTs and adriamycin with lipids at the same time. In this paper, SWNTs was modified with lysine lys, then the formulation and preparation process of Lys/CNTs-DOX-Lip compound were studied. The results showed that the final prescription was: the mass ratio of phospholipid to cholesterol was 5: 1, the ratio of drug to lipid was 1: 10, the detection time was 2 min, and the ratio of liposome to carbon tube was 2: 1. The final appearance of the composite preparation was black and red solution, and it was stably placed. The entrapment efficiency of the preparation was determined by ultrafiltration method. The final concentration of carbon nanotubes was about 200 渭 g ml-1, and the concentration of adriamycin was about 1mg ml-1. The pharmacological properties were studied. The particle size was 223 卤5.9 nm and the potential was -20 卤2.3 MV. The effects of different pH conditions on the drug release behavior were investigated in vitro. The results showed that the Lys/CNTs-DOX-Lip compound had obvious slow-release properties and had certain pH sensitivity. In this study, SD rats were used as model animals to determine the drug concentration in plasma by HPLC method, and to study the pharmacokinetic characteristics of Lys/CNTs-DOX-Lip compound preparation in vivo. The results showed that Lys / CNTs-DOX-Lip had a certain slow-release effect, prolonged the action time and improved the bioavailability compared with the DOX solution group. In this study, S180 tumor bearing mice were used as model animals. The distribution of Lys/CNTs-DOX-Lip compound preparation in tumor bearing mice was studied by HPLC. The results showed that the compound preparation had certain tumor targeting and reduced cardiac toxicity. At the same time, the effects of Lys/CNTs-DOX-Lip compound preparation and DOX control solution on the quality of life of S180 tumor bearing mice were investigated. The relative tumor volume, body weight, survival rate, drinking water, diet and so on were used as evaluation indexes. Liver, spleen, lung, kidney, brain, tumor and other main tissues were analyzed by HE staining to investigate the toxicity of the drug delivery system to the main organs of mice. The results showed that the Lys / CNTs-DOX-Lip preparation group had a good antitumor effect, and had no effect on the body weight and daily drinking diet of mice, and had a good mental state. The results of HE staining showed that Lys / CNTs-DOX-Lip had no obvious toxicity to the main organs of mice in the dose range.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【参考文献】