生物素化膽甾醇基普魯蘭糖的合成設(shè)計(jì)及作為藥物納米載體初步安全性評(píng)價(jià)
發(fā)布時(shí)間：2018-07-16 17:11
【摘要】：膽甾醇基普魯蘭糖具有兩親性，能在水中自聚集成納米粒，可用作抗腫瘤藥物的納米載體，達(dá)到被動(dòng)靶向腫瘤的作用。為進(jìn)一步提高抗瘤藥物療效并降低毒副作用，本文在膽甾醇基普魯蘭糖材料上連接生物素靶頭，設(shè)計(jì)合成主動(dòng)靶向的納米載體材料，對(duì)合成新型材料進(jìn)行結(jié)構(gòu)表征，并初步評(píng)價(jià)生物素化膽甾醇基普魯蘭糖的生物安全性。主要內(nèi)容如下： 通過酯化反應(yīng)在膽甾醇基普魯蘭糖（CHSP）多糖分子鏈游離羥基上接枝生物素分子，獲得兩親性質(zhì)的生物素化膽甾醇基普魯蘭糖（Bio-CHSP），通過核磁共振氫譜（1H-NMR）、傅里葉紅外（FT-IR）和X射線粉末衍射（XRD）對(duì)合成材料的分子結(jié)構(gòu)進(jìn)行表征。經(jīng)1H-NMR測定，合成生物素的取代度分別為38.9、29.2和20.1的三種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為100-180nm球形納米粒，穩(wěn)態(tài)熒光探針法測定其臨界聚集濃度（cac），cac值隨Bio-CHSP材料生物素取代度的增大而減小且Bio-CHSP材料自聚集納米粒粒徑隨著生物素取代度增大而減小。 以米托蒽醌（MTO）為模型藥物，采用透析法制備Bio-CHSP材料載藥納米粒。載藥納米粒的粒徑隨Bio-CHSP材料的生物素取代度增大而減�。划�(dāng)Bio-CHSP材料的生物素取代度一定，投藥藥載比不會(huì)顯著影響載藥納米粒的粒徑變化，但載藥量隨載體量加大而增大，包封率卻減小�？疾熵�(fù)載MTO的Bio-CHSP-29.2納米粒在不同pH緩沖液的釋放行為，隨著pH值降低，MTO釋放明顯加快；相比10h釋放90%以上的游離藥物，載藥納米粒呈雙相釋放行為，顯示出一定的緩釋性。 為初步考察Bio-CHSP材料的生物安全性，將Bio-CHSP納米粒溶液（200mg/kg）通過尾靜脈注射到昆明種小鼠體內(nèi)，通過實(shí)驗(yàn)組與空白對(duì)照組的小鼠生命體征，如體重、食量及小鼠主要臟器的病理切片觀察與對(duì)比，未見顯著差異，，故新合成的Bio-CHSP材料具備初步的生物安全性。
[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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5
本文編號(hào)：2127055
[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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5
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