環境敏感型磁性奈米顆粒之研製與藥物釋放性質研究 I.以無乳化劑乳化聚合法合成中空磁性奈米顆粒 II.以活性聚合法合成自組裝奈米顆粒

Abstract

本研究利用兩種方法製備組成中含有氮-異丙基丙烯醯胺與丙烯酸類衍生物之乳膠顆粒，藉由聚-氮-異丙基丙烯醯胺對於溫度的感應性質與丙烯酸類對於酸鹼的感應性質，合成對於環境變化產生感應之藥物載體。 第一種方法以無乳化劑乳化聚合法合成具空心結構之雙層磁性高分子顆粒。作為核心的聚甲基丙烯酸甲酯與與聚甲基丙烯酸共聚合物，外層包覆具交聯之聚異丙基丙烯醯胺與聚甲基丙烯酸共聚合物；鹼處理後，未交聯核心被洗去形成中空顆粒結構，再於此中空顆粒上添加磁性顆粒並討論合成起始酸鹼值之影響；最後合成第二層殼層包覆固定磁流體並穩定顆粒表面性質，得到雙層磁性中空奈米顆粒。實驗結果發現較鹼環境進行第二層高分子合成時，羧基讓顆粒表面有較好的分散性，包覆較均勻；若進料中羧基單體過少，合成產物與磁性粒子間正負電性之吸引力較小，便容易產生大量自成核於顆粒外。藥物釋放方面，酸性環境時，未解離之羧基導致顆粒緊縮且疏水，載藥或藥物釋放效果較差；高溫時，聚異丙基丙烯醯胺的疏水現象發生，顆粒更加緊縮，此環境下藥物釋放初期發生突釋；鹼性環境下，顆粒親水性提升，高溫時聚異丙基丙烯醯胺的疏水性質被競爭漸弱，溫度感應性質較不明顯，突釋現象也因此減緩許多。 第二種方法以可逆性分裂加成鏈轉移活性聚合法合成聚(異丙基丙烯醯胺-丙烯酸)之嵌段共聚合物。高溫時，聚異丙基丙烯醯胺呈疏水態，聚丙烯酸則為親水；藉由親疏水性質的差異進行自組裝以製備具溫度與酸鹼感應性質之顆粒。實驗結果發現鏈段轉移劑使氧化還原之起始系統對分子量可以有更好的控制，聚合度分佈也控制在1.3以下；且合成之聚異丙基丙烯醯胺末端被改質為羧基，使高分子鏈段具酸鹼及溫度感應性質；鹼性環境中，最低臨界溶解溫度升高；隨分子量增加，酸鹼感應性質則不明顯。此法合成之聚異丙基丙烯醯胺與聚乙烯酸嵌段共聚合物在不同比例下的自組裝型態亦被探討與觀察。

In this study, stimuli responsive latex nanoparticles composed of copolymers of N-isoprylacrylamide(NIPAAm) and acrylic acid(AA) derivatives were synthesized by two methods. Because of the thermo-sensitivity of polyNIPAAm and the pH-sensitivity of polyAA derivatives, these nanoparticles which is sensitive to both temperature and pH can be used in drug release system as a drug carrier. In the first method, emulsifier-free emulsion polymerization were used to synthesize magnetic hollow particles composed of random copolymer of NIPAAm and methacrylic acid(MAA) . Particle morphology. drug loading and release behavior were discussed. The magnetic hollow particles which can respond to temperature and pH were synthesized successful. The largest drug release percentage was found in the condition of room temperature and basic system. The drug bust phenomena occurred when particles were put into acidic solution. In the second method, well-defined living block copolymer of PNIPAAm and PAA was synthesized by Reversible Addition-Fragmentation Ttransfer (RAFT) to achieve self-assembly behavior at high temperature. When the poly(NIPAAm-b-AA) aqueous solution was heated, various morphologies in different ratios of PNIPAAm and PAA were observed due to the hydrophobic nature of PNIPAAm above its LCST. Sensitivities of temperature and pH were also confirmed in the lowest critical solution temperature experiment.