生物素化膽甾醇基普魯蘭糖的合成設計及作為藥物納米載體初步安全性評價
發(fā)布時間：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，達到被動靶向腫瘤的作用。為進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，設計合成主動靶向的納米載體材料，對合成新型材料進行結構表征，并初步評價生物素化膽甾醇基普魯蘭糖的生物安全性。主要內容如下： 通過酯化反應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）對合成材料的分子結構進行表征。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小；當Bio-CHSP材料的生物素取代度一定，投藥藥載比不會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。考察負載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，通過實驗組與空白對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.
【學位授予單位】：河北大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5
本文編號：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.
【學位授予單位】：河北大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5
【參考文獻】
相關期刊論文 前9條
1 陳紅麗;唐紅波;楊文智;陳漢;王銀松;梅林;張彤;熊青青;張其清;;生物素化殼聚糖修飾的PLGA納米粒的制備及表征[J];高等學�；瘜W學報;2010年08期
2 原續(xù)波,顧鳴岐,原艷波,李弘,王來好,盛京;膽固醇疏水改性殼聚糖自聚集納米微粒的制備及其動物體內分布研究[J];高分子通報;2005年05期
3 史艷萍;李學敏;陳寶泉;黃玉萍;張其清;;生物素化普魯蘭多糖納米顆粒制備與表征[J];功能材料;2009年01期
4 蘆殿香;樊渝江;;普魯蘭多糖在藥物釋放系統(tǒng)中的應用[J];化學研究與應用;2008年12期
5 閆永波;王中彥;李留法;韓楓;徐凱;莫鳳奎;;生物素化殼聚糖材料的合成及表征[J];山東大學學報(醫(yī)學版);2009年05期
6 高嫻;馬世坤;;殼聚糖作為藥物緩釋控釋載體的研究進展[J];生命科學;2008年04期
7 于燕;顏虹;胡森科;張振軍;孫曉英;;納米材料的安全性評價[J];中國臨床康復;2006年01期
8 劉占軍;張衛(wèi)國;于九皋;韓剛;代紅光;;負載紫杉醇殼聚糖納米粒的制備、表征與釋藥性能[J];中國組織工程研究與臨床康復;2009年03期
9 楊文智;李學敏;陳紅麗;陳名懋;劉玲蓉;張其清;;膽甾醇基-普魯蘭多糖疏水改性材料的制備及其自組裝性質的研究[J];中國新藥雜志;2009年01期
本文編號：2127055
本文鏈接：http://www.sikaile.net/yixuelunwen/yiyaoxuelunwen/2127055.html
最近更新
教材專著
