本文關(guān)鍵詞： 白芨多糖 兩親性聚合物 聚合物膠束 載藥量 包封率　出處：《吉林大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：為增加白芨多糖的疏水性,以硬脂酸對(duì)白芨多糖進(jìn)行疏水修飾,制備了白芨多糖兩親性聚合物(SA-BSPs)藥物載體。采用紅外光譜及氫核磁共振光譜對(duì)其進(jìn)行表征,其取代度利用氫核磁共振光譜中峰面積進(jìn)行計(jì)算。并以多西他賽為模型藥物,采用溶劑揮發(fā)法制備多西他賽硬脂酸修飾白芨多糖(DTX-SA-BSPs)膠束,采用激光粒度測(cè)定儀對(duì)膠束粒徑、粒度分布及zeta電位進(jìn)行測(cè)定。以高效液相色譜法(HPLC)測(cè)定其載藥量及包封率。采用透析法對(duì)其體外釋放度進(jìn)行考察。小鼠單劑量尾靜脈注射給予DTX-SA-BSPs聚合物膠束及多西他賽注射液,采用高效液相色譜法測(cè)定不同時(shí)間點(diǎn)血藥濃度,繪制藥-時(shí)曲線,使用DAS2.1藥動(dòng)學(xué)軟件進(jìn)行相關(guān)藥動(dòng)學(xué)參數(shù)的計(jì)算,考察其在小鼠體內(nèi)藥動(dòng)學(xué)。測(cè)定各組織臟器中藥物濃度,評(píng)價(jià)多西他賽制成膠束后其在小鼠體內(nèi)的分布。通過MTT法和紅細(xì)胞溶血實(shí)驗(yàn)對(duì)硬脂酸修飾的白芨多糖衍生物進(jìn)行初步生物安全性評(píng)價(jià)。結(jié)果表明,硬脂酸已成功接枝到白芨多糖的羥基上,取代度為12.94%。DTX-SA-BSPs聚合物膠束平均粒徑為(97.01±3.17)nm,zeta電位為(-19.56±0.22)mV、載藥量為(9.13±0.17)%、包封率達(dá)(81.11±0.18)%。結(jié)果表明,在pH7.4磷酸鹽緩沖液中多西他賽從膠束釋放量隨時(shí)間延長(zhǎng),體外累積釋藥量逐漸增加,在48 h時(shí)體外累積釋藥量達(dá)到(66.93±1.79)%,且呈現(xiàn)出緩慢釋放的特性。MTT實(shí)驗(yàn)表明,0.5μg/mL DTX-SA-BSPs聚合物膠束孵育72 h時(shí),肝癌細(xì)胞抑制率為(83.7±1.0)%,對(duì)肝癌細(xì)胞具有一定的抑制作用。小鼠體內(nèi)藥代動(dòng)力學(xué)研究結(jié)果表明,DTX-SA-BSPs聚合物膠束相較于多西他賽注射液在小鼠體內(nèi)具有更高的血藥濃度、更長(zhǎng)的維持時(shí)間(MRT 1.42±0.02h vs 1.82±0.11 h,p0.05),絕對(duì)生物利用度是多西他賽注射液的1.39倍(AUC0-∞65.39±5.21μg/mL·h vs 47.73±0.49μg/mL·h,p0.05)。組織分布實(shí)驗(yàn)表明,DTX-SA-BSPs聚合物膠束在心、肝、肺組織具有較高的藥物分布,而在脾、腎藥物分布較低,表明DTX-SA-BSPs聚合物膠束可改變藥物的組織分布,是一種治療癌癥的可用方法。
[Abstract]:In order to increase the hydrophobicity of Bletilla striata polysaccharide, stearic acid was used to modify Bletilla striata polysaccharide hydrophobically. The amphiphilic polymer of Bletilla striata polysaccharide SA-BSPswas prepared and characterized by IR and HNMR. The degree of substitution was calculated by means of peak area in hydrogen nuclear magnetic resonance spectroscopy, and docetaxel was used as model drug to prepare DTX-SA-BSPs micelles modified with docetaxel stearic acid by solvent volatilization. The micelle size was measured by laser particle size analyzer. The particle size distribution and zeta potential were measured. The drug loading and entrapment efficiency were determined by HPLC. The release in vitro was investigated by dialysis. Single dose tail vein injection of DTX-SA-BSPs polymer micelle and docetaxel injection was used in mice. High performance liquid chromatography (HPLC) was used to determine the drug concentration at different time points and draw the drug-time curve. The pharmacokinetic parameters were calculated by DAS2.1 software, and the pharmacokinetics in mice was investigated. To evaluate the distribution of docetaxel micelles in mice. The biological safety of stearic acid modified Bletilla striata polysaccharide derivatives was evaluated by MTT method and erythrocyte hemolysis test. Stearic acid was successfully grafted onto the hydroxyl groups of Bletilla striata polysaccharides. The degree of substitution was 12.94. The average particle size of DTX-SA-BSPs polymer micelles was 97.01 鹵3.17nmmZeta potential was -19.56 鹵0.22mV, the drug loading capacity was 9.13 鹵0.17mV, the entrapment efficiency was 81.11 鹵0.180.The results showed that. In pH7.4 phosphate buffer, the amount of docetaxel released from micelles increased with time, and the cumulative release of docetaxel gradually increased with time. At 48 h, the cumulative drug release reached 66.93 鹵1.79%, and showed slow release. The results showed that 0.5 渭 g / mL DTX-SA-BSPs polymer micelles were incubated for 72 h. The inhibition rate of hepatoma cells was 83.7 鹵1.0, which had a certain inhibitory effect on hepatoma cells. The results of pharmacokinetic study in mice showed that DTX-SA-BSPs polymer micelles had higher blood drug concentration than docetaxel injection in mice. The longer maintenance time was 1.42 鹵0.02 h vs 1.82 鹵0.11 h (p 0.05), and the absolute bioavailability was 1.39 times higher than that of docetaxel injection. AUC0- 鈭，

本文編號(hào)：1529262