- 學位論文
以葉酸標的之聚乙二醇-聚乳酸二團聯共聚物合成及其高分子微胞之研究
The Study of Polymeric Micelles Based on Folate-Poly(ethylene glycol)-Poly(L-lactic acid) and Methoxy Poly(ethylene glycol)-Poly(L-lactide) Copolymer
摘要
近年來，利用生分解性高分子合成出兩性團聯共聚物，並且使其在水相溶液中自組裝(self-assembly)為高分子微胞的系統越來越受到矚目。因為這樣的微胞具有粒子小，延長體內循環時間，提高藥物包覆率等特性，而在藥物傳輸系統上有很大的應用空間。 本研究即利用兩種通過FDA認可具有生物相容性的高分子：mPEG與PLLA，利用開環聚合法(ring-opening polymerization)合成出不同親疏水鏈長比的mPEG-PLLA二團聯共聚物：mPEGLA4k、mPEGLA6k與mPEGLA8k。並且利用fluorescence probe techniques測得此類高分子微胞具有極小的CMC，因此有較高的穩定性。將合成好的高分子，利用乳化法(o/w emulsion method)來製備高分子微胞。經過篩選之後，選擇以mPEGLA6k高分子作為形成微胞主要的結構。而為了使高分子微胞具有標的性質，研究中亦成功的合成出接枝有葉酸基團的FA-PEG-PLLA團聯共聚物，與mPEGLA6k二團聯共聚物混合形成具有標的特性的高分子微胞。所製備好的高分子微胞，混合葉酸前後的大小分別為127.3 ± 11.1 nm與121.3 ± 7.8 nm，並且兩組系統的降解皆是以極緩慢的形式進行，以及具有良好的穩定性(可維持30天)。 在包覆疏水性藥物Camptothecin方面，兩組微胞系統在包覆藥物 前後粒徑約增加20 nm，並且包覆效率皆為13 %左右。若以高分子材料為基準計算，則1 mg的高分子可以包覆6.5 μg的CPT。藥物釋放的機制是以擴散(diffusion)的方式，在兩小時之內，約釋放了40%，而經過四小時，即釋放了60 %，一直到一天之後，大部分的CPT都已經釋放完全。
並列摘要
Amphiphilic block copolymers which synthesized from biodegradable polymers have been explored in recent years. In an aqueous environment, they can self-assemble into polymeric micelles. Due to their characteristics such as small particle size, long-circulation time and enhanced drug loading efficiency, micelles are widely used in drug delivery system. In this study, the diblock copolymers mPEG-PLLA were synthesized by ring-opening polymerization. The copolymers with different hydrophilic and hydrophobic chain length have been named as mPEGLA4k, mPEGLA6k and mPEGLA8k. Moreover, critical micelle concentration (CMC) have been measured by fluorescence probe techniques. The polymeric micelles were prepared by o/w emulsion method, and the mPEGLA6k polymer was chosen to be the main material of micelles during a series of experiments. Besides, folate-conjugated PEG-PLLA was also synthesized in this study, and this polymer was mixed with mPEGLA6k to form the targeting polymeric micelles. The particle size of mPEGLA6k micelle was 127.3 ± 11.1 nm and that of targeting micelle was 121.3 ± 7.8 nm. The degradation rate of both systems were very slow, and there were no significant size change for 30 days, which showed high stability. The particles size of two micelle systems encapsulated with camptothecin were 20 nm large than micelles without drug, and the encapsulation efficiency were both about 13 %. The results implied that the drug release from micelles was mainly controlled by diffusion. Nearly 40 % of drug released in 2 hours while the rest drug released within 1 day.