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標題: | 環境敏感型幾丁聚醣奈米顆粒合成、性質與應用研究 Synthesis and Characterization of Stimuli-Responsive Chitosan-Based Nanoparticles |
作者: | Chung-Yang Chuang 莊仲揚 |
指導教授: | 邱文英(Wen-Yen Chiu) |
關鍵字: | 幾丁聚醣,丙烯酸,氮-異丙基丙烯醯胺,奈米顆粒,自組裝,環境敏感,控制釋放, chitosan,acrylic acid,N-isopropylacrylamide,stimuli-responsive,controlled release,nanoparticles,self-assembly, |
出版年 : | 2010 |
學位: | 博士 |
摘要: | 本研究是利用化學設計方法,將幾丁聚醣與環境敏感型高分子加以結合,製備出不同結構與形態的環境敏感型幾丁聚醣奈米顆粒,藉由反應條件控制,本研究成功合成出中空結構、多孔結構以及實心結構的環境敏感型奈米顆粒,並分別探討其生成機制、顆粒結構形態、環境應答特性以及應用於藥物控制釋放載體之可行性。
(一)pH敏感型幾丁聚醣中空奈米顆粒 在此是利用無乳化劑乳化聚合方式,以過硫酸鉀作為起始劑,將丙烯酸單體與幾丁聚醣進行聚合反應,生成幾丁聚醣-聚丙烯酸奈米顆粒,並探討所合成顆粒之結構形態、環境應答特性以及應用於藥物控制釋放載體與酸鹼緩衝材料之可行性。實驗發現,所合成之幾丁聚醣-聚丙烯酸奈米顆粒表面帶有正電,在特定幾丁聚醣/丙烯酸進料組成之下所合成之顆粒,呈現中空結構。顆粒形態與粒徑會隨不同進料組成而有所改變,且具備酸鹼應答特性,可應用於酸鹼緩衝材料,另外,幾丁聚醣-聚丙烯酸奈米顆粒應用於藥物控制釋放載體上,具有長時間釋放之效果,且在不同pH值環境下,釋放行為亦有所差異。 (二)pH/溫度雙重敏感型幾丁聚醣實心奈米顆粒 本部分是將丙烯酸單體與氮-異丙基丙烯醯胺單體,以過硫酸鉀為起始劑,利用無乳化劑乳化聚合方式與幾丁聚醣進行共聚合反應,生成幾丁聚醣-聚(丙烯酸-co-氮-異丙基丙烯醯胺)奈米顆粒,並探討所合成顆粒之形成機制、結構形態、環境應答特性以及應用於藥物控制釋放載體之可行性。實驗發現,所合成之幾丁聚醣-聚(丙烯酸-co-氮-異丙基丙烯醯胺)奈米顆粒表面帶有正電,且顆粒結構由中空轉為實心。顆粒形態與粒徑會隨不同進料組成而有所改變,且在不同溫度以及II酸鹼環境下,所合成之顆粒其粒徑與表面電位都會隨之變化,表示顆粒同時具備溫度敏感以及酸鹼敏感之特性,另外,幾丁聚醣-聚(丙烯酸-co-氮-異丙基丙烯醯胺)奈米顆粒應用於藥物控制釋放載體上,具有長時間釋放之特性,且在不同釋放環境下,其藥物釋放曲線也會有所改變。 (三)自組裝法製備環境敏感型幾丁聚醣微多孔奈米顆粒 此處是將氮-異丙基丙烯醯胺單體,以硝酸銨鈰為起始劑,利用接枝聚合方式與幾丁聚醣進行共聚合反應,生成幾丁聚醣-聚(氮-異丙基丙烯醯胺)接枝共聚物/聚(氮-異丙基丙烯醯胺)自聚物混合溶液,經適當稀釋與特殊環境下,利用自組裝的方式,生成幾丁聚醣-聚(氮-異丙基丙烯醯胺)奈米顆粒,並探討所合成顆粒之形成機制、結構形態、環境應答特性以及應用於藥物控制釋放載體之可行性。實驗發現,所合成之幾丁聚醣-聚(氮-異丙基丙烯醯胺)奈米顆粒表面帶有正電,且顆粒內部呈現微多孔結構。顆粒粒徑會隨共聚物組成而有所改變,且在不同溫度以及酸鹼環境下,顆粒粒徑與表面電位都會隨之變化,表示該顆粒同時具備溫度敏感以及酸鹼敏感之特性,另外,幾丁聚醣-聚(氮-異丙基丙烯醯胺)奈米顆粒應用於藥物控制釋放載體上,由於結構為微多孔形態,因此顆粒載藥量可明顯提升,且同時具備長時間釋放之效果,在不同釋放環境下,其藥物釋放曲線也會有所差異,具有控制釋放之能力。 (四)接枝共聚物分子自組裝製備環境敏感型幾丁聚醣多孔/中空奈米顆粒 在此是將氮-異丙基丙烯醯胺單體,以硝酸銨鈰為起始劑,利用接枝聚合方式與幾丁聚醣進行共聚合反應,生成幾丁聚醣-聚(氮-異丙基丙烯醯胺)接枝共聚物/聚(氮-異丙基丙烯醯胺)自聚物,將聚(氮-異丙基丙烯醯胺)自聚物移除後,在適當共聚物濃度與環境下,利用自組裝的方式生成幾丁聚醣-聚(氮-異丙基丙烯醯胺)多孔/中空奈米顆粒,並探討所合成顆粒之形成機制、結構形態、環境應答特性以及應用於藥物控制釋放載體之可行性。實驗發現,所合成之幾丁聚醣-聚(氮III-異丙基丙烯醯胺)多孔/中空奈米顆粒表面帶有正電,且顆粒會隨環境溫度不同,內部結構呈現多孔/中空之變化。顆粒形態與粒徑會隨共聚物接枝分子量以及組成不同而有所改變,且在不同溫度以及酸鹼環境下,顆粒粒徑與表面電位都會隨之變化,表示顆粒同時具備溫度敏感以及酸鹼敏感之特性,另外,幾丁聚醣-聚(氮-異丙基丙烯醯胺)多孔/中空奈米顆粒應用於藥物控制釋放載體上,由於結構為多孔/中空形態,因此可有效提高顆粒載藥量,同時具有長時間釋放之效果,在不同釋放環境下,其藥物釋放曲線也會有所改變,具有控制釋放之能力。 (五)環境敏感型幾丁聚醣奈米顆粒藥物釋放行為模擬 本部分則是依實驗所製得奈米顆粒結構與形態,以質量傳遞模型進行藥物釋放量與時間關係之理論推導,並與實驗所得各類型奈米顆粒之藥物釋放曲線比較,計算所包覆藥物於奈米顆粒中之擴散係數。實驗發現,藥物於奈米顆粒之中的擴散係數,與顆粒結構以及藥物釋放所在環境溫度與酸鹼值有關。 In this research, chitosan-based stimuli-responsive nanoparticles were prepared by different polymerization method. Structure, morphology, environmental sensitive behavior and application in drug release were studied in this research. In the first part, polyelectrolyte complex particles of chitosan-poly(acrylic acid) (CS-PAA) through polymerization of acrylic acid (AA) in the presence of chitosan (CS). The prepared CS-PAA complex particles had positive zeta potential and dispersed very well in the aqueous solution. Structure and morphology of complex particles were investigated with the changes in the feeding molar ratio of glucosamine unit in CS to AA monomer. It was found at a molar ratio of 1.0/1.1, a hollow structure in complex particles was observed after polymerization. The synthesized complex particles were environmentally sensitive in which their mean diameter could change with the pH value of medium. Moreover, the complex particles showed a continuous release of the encapsulated doxycycline hyclate up to 8 days. These complex particles with environmentally sensitive properties are expected to be utilized in the hydrophilic drug delivery system. In the second part, thermo- and pH-responsive chitosan-based nanoparticles were synthesized via the surfactant-free emulsion polymerization. The thermal/pH dual responsive properties of these nanoparticles were designed by the addition of a pH sensitive monomer, acrylic acid (AA), to be copolymerized with N-isopropylacrylamide (NIPAAm) in a chitosan (CS) solution. The molar ratio of CS/AA/NIPAAm in the feed was changed to investigate its effect on structure, morphology, thermo- and pH-responsive properties of the nanoparticles. It was found that CS-PAA-PNIPAAm nanoparticles could be well dispersed in the aqueous solution and carried positive charges on the surface. The addition of thermal-sensitive NIPAAm monomer affected the polymerization mechanism and interactions between CS and AA. The particle size of the nanoparticles was found to be varied with the composition of NIPAAm monomer in the feed. The synthesized nanoparticles exhibited stimuli-responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in-vitro release experiment. The environmentally responsive nanoparticles are expected to be utilized in many fields such as drug delivery system. In the third part, thermo- and pH-responsive chitosan-based porous nanoparticles were prepared by the temperature-dependent self assembly method. The chitosan-graft-poly(N-isopropylacrylamide) (CS-g-PNIPAAm) copolymer solution was prepared through polymerization of N-isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using cerium ammounium nitrate as the initiator. Then, CS-g-PNIPAAm solution was diluted by deionized water and heated to 40℃ for CS-g-PNIPAAm self-assembly. After that, CS-g-PNIPAAm assembled to form micelles in which shell layer was CS. Crosslinking agent was used to reinforce the micelle structure to form nanoparticle. The molar ratio of CS/NIPAAm in the feed mixture was changed to investigate its effect on structure, morphology, thermo- and pH-responsive properties of the nanoparticles. TEM images showed that a porous structure of nanoparticles was developed. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli-responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in-vitro release experiment. These porous particles with environmentally sensitive properties are expected to be utilized in hydrophilic drug delivery system. In the fourth part, stimuli-responsive porous/hollow nanoparticles were prepared by the self assembly of CS-based graft copolymers. The chitosan-graft-poly(N-isopropylacrylamide) (CS-g-PNIPAAm) copolymer solution was prepared through polymerization of N-isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using cerium ammounium nitrate as the initiator. Then, CS-g-PNIPAAm copolymers were dissolved in acetic acid aqueous solution and heated to 40℃ for CS-g-PNIPAAm self-assembly. After that, CS-g-PNIPAAm assembled to form micelles and crosslinking agent was used to reinforce the micelle structure to form nanoparticles. The molecular weight of grafted PNIPAAm on CS chains was changed to investigate its effect on structure, morphology, thermal- and pH-responsive properties of the nanoparticles. TEM images showed that a porous or hollow structure in the interior of nanoparticles was developed. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli-responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in-vitro release experiment. These porous/hollow particles with environmentally sensitive properties are expected to be utilized in drug release. In the fifth part, the model of drug release behavior of CS-based nanoparticles was developed from Fick’s second law. According to the structure and the release environment of nanoparticles, the theoretical relationship between drug release amount and release time for different structure CS-based nanoparticles was developed. Compared with experiment results, the range of diffusivity for encapsulated-drug in the nanoparticles was evaluated. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46665 |
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