【摘要】：纖維素以其良好的生物相容性、可生物降解性等優(yōu)點,在生物醫(yī)藥領域中有著廣泛的應用。通過對纖維素進行接枝改性,在其結構中引入pH敏感性基團,可使得到的纖維素聚合物膠束能夠根據(jù)人體不同部位的pH特點,實現(xiàn)對其所負載藥物的靶向釋放,提高藥物的生物利用度,減小藥物對人體的毒副作用。因此,本研究以纖維素的良好溶劑離子液體為反應介質,并結合原子轉移自由基聚合(ATRP)反應過程活性可控的技術優(yōu)點,在纖維素分子中均勻地接枝了不同的pH敏感性分子,以期更好地實現(xiàn)pH響應性纖維素聚合物膠束在不同生理環(huán)境下對藥物的緩、控釋效果。本研究在離子液體氯化-1-烯丙基-3-甲基咪唑([AMIM]Cl)中,通過ATRP法在微晶纖維素分子骨架上分別均勻地接枝了聚4-乙烯基吡啶和聚甲基丙烯酸叔丁酯分子,并通過聚甲基丙烯酸叔丁酯水解為聚甲基丙烯酸,分別得到了具有pH響應性的弱堿性MCC-g-P4VP和弱酸性MCC-g-PMAA聚合物分子,優(yōu)化了兩種產(chǎn)物的合成工藝條件。通過FT-IR、1H NMR,確定了產(chǎn)物的分子結構;GPC測得聚合物的側鏈分子的分子量分布窄,大小均勻。采用表面張力法,測得MCC-g-P4VP和MCC-g-PMAA聚合物膠束均具有較小的臨界膠束濃度(CMC),穩(wěn)定性較好;通過TEM、DLS和UV-Vis對兩種聚合物自組裝膠束的粒徑、形貌及pH響應性進行了研究,結果表明:兩種聚合物可自組裝成球狀結構膠束,膠束的流體力學直徑小于200納米、粒徑分布均勻。兩種聚合物膠束在不同pH條件下的粒徑及透光率均表現(xiàn)出了相應的轉變,具有良好的pH響應性。分別以親水性的羅丹明B(Rh B)和疏水性的阿司匹林(ASP)為模型藥物,對MCC-g-P4VP和MCC-g-PMAA膠束的藥物包覆性能及在不同pH條件下的藥物控釋性能進行了分析,并結合動力學模型對比分析了兩種聚合物膠束在不同pH條件下對水溶性不同藥物的釋放機制,結果表明:MCC-g-P4VP膠束對兩種藥物具有良好的包覆性能,載藥后膠束具有核-殼狀的球形結構,載藥膠束在酸性條件下的累積藥物釋放量大于堿性條件,且在酸性條件下的體外藥物釋放符合一級動力學方程,在中性和堿性條件的藥物釋放符合Ritger-Pappas方程;MCC-g-PMAA載藥膠束在堿性條件下的累積藥物釋放量大于酸性條件,表現(xiàn)出了良好的藥物控釋性能,藥物釋放動力學方程擬合結果表明,酸性和中性條件下,MCC-g-PMAA膠束對兩種藥物的釋放符合擴散和溶蝕相結合的機制;堿性條件下對兩種藥物的釋放為擴散機制。
[Abstract]:Cellulose has been widely used in the field of biomedicine because of its good biocompatibility and biodegradability. Through the graft modification of cellulose and the introduction of pH sensitive groups into its structure, the cellulose polymer micelles can achieve the targeted release of the drugs loaded on the cellulose micelles according to the characteristics of pH in different parts of the human body. Improve the bioavailability of drugs, reduce the toxic side effects of drugs on the human body. Therefore, in this study, ionic liquids, a good solvent of cellulose, were used as reaction medium, and combined with the advantages of controllable activity of atom transfer radical polymerization (ATRP) reaction process, different pH sensitive molecules were evenly grafted into cellulose molecules. In order to realize the slow and controlled release effect of pH responsive cellulose polymer micelles in different physiological environment. In this paper, poly (4-vinylpyridine) and poly (tert-butyl methacrylate) were grafted uniformly on the framework of microcrystalline cellulose by ATRP method in ionic liquid chloride-1-allyl-3-methylimidazole ([AMIM] Cl). Through hydrolysis of poly (tert-butyl methacrylate) to poly (methacrylic acid), weak basic MCC-g-P4VP and weak acid MCC-g-PMAA polymers with pH response were obtained respectively. The synthesis conditions of the two products were optimized. The molecular structure of the product was determined by FT-IR,1H NMR, and the molecular weight distribution of the side chain molecule of the polymer was narrow and uniform by GPC. By using surface tension method, it was found that both MCC-g-P4VP and MCC-g-PMAA micelles had better stability of (CMC), with lower critical micelle concentration. The particle size, morphology and pH response of two kinds of self-assembled micelles were studied by TEM,DLS and UV-Vis. The results showed that the two polymers could be self-assembled into spherical micelles, and the diameter of micelles was less than 200nm, and the diameter of micelles was less than 200nm. The particle size distribution is uniform. The particle size and transmittance of the two kinds of polymer micelles under different pH conditions showed corresponding changes and had good pH response. Using Rhodamine B (Rh B) and hydrophobic aspirin (ASP) as model drugs, the drug-coated properties of MCC-g-P4VP and MCC-g-PMAA micelles and their controlled-release properties under different pH conditions were analyzed. The release mechanism of two kinds of polymer micelles to water-soluble and different drugs under different pH conditions was compared and analyzed with kinetic model. The results showed that MCC-g-P4VP micelles had good coating properties for two kinds of drugs. The drug-loaded micelles have a spherical core-shell structure. The cumulative drug release of drug-loaded micelles in acidic condition is larger than that in alkaline condition, and the drug release in vitro accords with the first-order kinetic equation under acidic conditions. The drug release in neutral and alkaline conditions was in accordance with the Ritger-Pappas equation. The cumulative drug release of MCC-g-PMAA micelles in alkaline condition was higher than that in acidic condition, and showed a good controlled release performance. The results of drug release kinetics equation fitting showed that under acidic and neutral conditions, the drug release rate of micelles was higher than that of acidic micelles. The release of MCC-g-PMAA micelles to the two drugs was consistent with the mechanism of diffusion and dissolution. The release of the two drugs under alkaline conditions is a diffusion mechanism.
【學位授予單位】：河北科技大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O636.11;TQ460.1

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