生物素化胆甾醇基普鲁兰糖的合成设计及作为药物纳米载体初步安全性评价

发布时间：2018-07-16 17:11

【摘要】：胆甾醇基普鲁兰糖具有两亲性，能在水中自聚集成纳米粒，可用作抗肿瘤药物的纳米载体，达到被动靶向肿瘤的作用。为进一步提高抗瘤药物疗效并降低毒副作用，本文在胆甾醇基普鲁兰糖材料上连接生物素靶头，设计合成主动靶向的纳米载体材料，对合成新型材料进行结构表征，并初步评价生物素化胆甾醇基普鲁兰糖的生物安全性。主要内容如下：通过酯化反应在胆甾醇基普鲁兰糖（CHSP）多糖分子链游离羟基上接枝生物素分子，获得两亲性质的生物素化胆甾醇基普鲁兰糖（Bio-CHSP），通过核磁共振氢谱（1H-NMR）、傅里叶红外（FT-IR）和X射线粉末衍射（XRD）对合成材料的分子结构进行表征。经1H-NMR测定，合成生物素的取代度分别为38.9、29.2和20.1的三种Bio-CHSP材料，即Bio-CHSP-38.9、Bio-CHSP-29.2和Bio-CHSP-20.1。Bio-CHSP材料能在水中自聚集为100-180nm球形纳米粒，稳态荧光探针法测定其临界聚集浓度（cac），cac值随Bio-CHSP材料生物素取代度的增大而减小且Bio-CHSP材料自聚集纳米粒粒径随着生物素取代度增大而减小。以米托蒽醌（MTO）为模型药物，采用透析法制备Bio-CHSP材料载药纳米粒。载药纳米粒的粒径随Bio-CHSP材料的生物素取代度增大而减小；当Bio-CHSP材料的生物素取代度一定，投药药载比不会显著影响载药纳米粒的粒径变化，但载药量随载体量加大而增大，包封率却减小。考察负载MTO的Bio-CHSP-29.2纳米粒在不同pH缓冲液的释放行为，随着pH值降低，MTO释放明显加快；相比10h释放90%以上的游离药物，载药纳米粒呈双相释放行为，显示出一定的缓释性。为初步考察Bio-CHSP材料的生物安全性，将Bio-CHSP纳米粒溶液（200mg/kg）通过尾静脉注射到昆明种小鼠体内，通过实验组与空白对照组的小鼠生命体征，如体重、食量及小鼠主要脏器的病理切片观察与对比，未见显著差异，，故新合成的Bio-CHSP材料具备初步的生物安全性。
[Abstract]:Because of its amphiphilic properties, cholesterol can self-aggregate into nanoparticles in water, and can be used as a nano-carrier of anti-tumor drugs to achieve the passive targeting of tumor. In order to further improve the curative effect of anti-tumor drugs and reduce the side effects, biotin targets were attached to the materials of cholesteryl pullulanose, and the active targeting nano-carrier materials were designed and synthesized, and the structure of the new materials was characterized. The biological safety of biotinylated cholerosterol was preliminarily evaluated. The main contents are as follows: the biotin molecules were grafted onto the free hydroxyl groups of CHSP polysaccharides by esterification reaction. Amphiphilic biotin cholosterol (Bio-CHSP) was obtained. The molecular structure of the synthesized materials was characterized by 1H-NMR, FT-IR and X-ray powder diffraction (XRD). Three Bio-CHSP materials, Bio-CHSP-38.9 and Bio-CHSP-29.2 and Bio-CHSP-20.1.Bio-CHSP can self-aggregate into 100-180nm spherical nanoparticles in water by 1H-NMR. The critical aggregation concentration (cac) of Bio-CHSP decreased with the increase of biotin substitution degree, and the particle size of Bio-CHSP self-aggregation nanoparticles decreased with the increase of biotin substitution by steady-state fluorescence probe method. Bio-CHSP nanoparticles were prepared by dialysis using mitoxantrone (MTO) as model drug. The particle size of the drug loaded nanoparticles decreased with the increase of biotin substitution degree of Bio-CHSP material, but the drug loading ratio did not significantly affect the particle size change of Bio-CHSP material, but the drug loading amount increased with the increase of the amount of carrier, while the drug loading ratio of Bio-CHSP material increased with the increase of the biotin substitution degree of Bio-CHSP material. The encapsulation efficiency is reduced. The release behavior of Bio-CHSP-29.2 nanoparticles loaded with MTO in different pH buffer solution was investigated. The release of MTO was accelerated with the decrease of pH value, and compared with the release of more than 90% of free drugs at 10 h, the drug loaded nanoparticles showed a biphasic release behavior, showing a certain slow-release ability. In order to investigate the biological safety of Bio-CHSP material, Bio-CHSP nanoparticles solution (200mg/kg) was injected into Kunming mice via tail vein, and the vital signs such as body weight of the experimental group and the blank control group were used. There was no significant difference in food intake and pathological sections of the main organs of mice, so the newly synthesized Bio-CHSP material had a preliminary biological safety.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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