Title

多功能接枝型聚胜肽共聚物製備及其結構性質之研究

Translated Titles

Studies on Synthesis, Structures, and Properties of Multifunctional Polypeptide Graft Copolymers

DOI

10.6844/NCKU.2011.00437

Authors

涂侑良

Key Words

聚胜肽 ; 巨單體 ; 接枝型共聚合物 ; 微胞 ; 藥物釋放 ; polypeptide ; macromonomer ; graft copolymer ; micelle ; drug release

PublicationName

成功大學化學工程學系學位論文

Volume or Term/Year and Month of Publication

2011年

Academic Degree Category

博士

Advisor

陳志勇

Content Language

繁體中文

Chinese Abstract

近年來生物可降解性高分子,如poly(ethylene glycol) (PEG)、poly(latic acid) (PLA)、poly(caprolactam) (PCL)及polypeptide等,由於可應用於醫藥及生物醫學材料領域,因此許多研究團隊對此種高分子具有相當大的興趣。其中,聚胜肽(Polypeptides)共聚合物於生化領域為最熱門的研究主題。其具有兩種以上不同的化學鏈段,擁有多樣化的性質。因此,本研究的目的即是製備出一系列接枝型聚胜肽共聚合物,除觀察研究其表面型態對溫度、pH值等環境因子的效應外,並進一步製備成奈米級的微胞,引入小分子藥物進行藥物的控制施放之研究。 本研究的第一部分以一級胺或一級胺鹽為親核試劑與Nε-benzyloxycarbonyl-L-lysine N-carboxyanhydrides (Z-Lys NCA,產率~70%)行開環聚合反應製備poly(Nε-benzyloxycarbonyl-L-lysine) (poly(Z-L-lysine), PZLLys,轉化率約89%);並將PZLLys的末端胺基改質為具有雙鍵的巨單體(Macromonomer),再與共單體行自由基聚合反應製備出一系列接枝型共聚合物poly(GMA)-graft-poly(Z-L-lysine) (PGMA-g-PZLLys) 及poly(NIPAm)-co-poly(L-lysine) (PNIPAm-co-PLLys)。實驗利用AFM、FTIR、WAXS及SAXS來分析其微結構和形態及接枝型共聚物PGMA-g-PZLLys中GMA的比例與poly(Z-L-lysine)側鏈聚合度的關係。AFM觀察結果顯示,n8-G89和n14-N43(側鏈DP分別為8及14,GMA比例分別為89%及43%的接枝型共聚合物)皆具有大小均勻的條狀結構;由FTIR的光譜圖中,可以發現共聚合物中的單體比例會影響其α-helix及β-sheet二級結構。然而X-ray的結果卻顯示出共聚合物的二級結構主要還是受到poly(Z-L-lysine)側鏈長度影響,且結果也和AFM所觀察到的現象相符。接著,以1H NMR、CD(Circular dichroism)、DLS(Dynamic light scatterning)、TEM、AFM等研究PNIPAm-co-PLLys於水溶液中的pH及溫度效應。實驗結果指出,L15-N30及L15-N70(側鏈DP皆為15,NIPAm比例分別為30 mol %及70 mol %)之pH值由pH 6變化到pH 12時,會有coil-to-helix的轉變,且可於pH 12、室溫下形成均一大小的奈米級微胞結構。而此接枝型共聚合物於pH 6、50oC下亦可因其有輕微的聚集而形成微胞結構。當溫度與pH值都上升時,PLLys和PNIPAm會由親水性變成疏水性的鏈段,而使得共聚合物沈澱。實驗結果說明本文已成功的合成出雙親水性接枝型共聚合物,且其在溫度或pH值上升時會因輕微的高分子聚集而形成微胞。 本研究的第二部分則是將接枝型共聚合物應用於藥物的控制釋放。本文將疏水性小分子抗癌藥物MTX (Methotrexate)與PNIPAm-co-PLLys鍵結,經1H NMR、DLS、TEM、AFM等分析結果顯示成功地得到雙親水性的高分子藥物載體,此藥物載體可以於水溶液中形成微胞。接著,使用天然交聯劑Genipin與PNIPAm-co-PLLys製備殼層交聯型微胞,並進一步將抗癌藥物MTX包覆至微胞內,以HPLC分析其包藥效率及包藥量。最後,在37oC、pH 7.4的緩衝溶液中進行藥物釋放的實驗。結果發現L15-N65交聯微胞的藥物累積釋放量可達90%以上,而L30-N75的藥物累積釋放量則約62~66 %。

English Abstract

A set of biodegradable polymers has recently been developed, including poly(ethylene glycol) (PEG), poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL) and polypeptides (poly(L-lysine) derivatives), and are of great interest for application in pharmaceutical and biomedical sciences. Among them, block and graft polypeptide copolymers are the most popular research topics for biomedical science because they usually contain two or more different chemical species, have diverse properties and assume controllable structures. In the first section of this study, poly(benzyloxycarbonyl-L-lysine) (poly(Z-L-lysine), conversion~89%) was prepared via ring-opening polymerization by using n-hexylamine or 4-vinylbenzyl amine hydrochloride as initiator with Nε-benzyloxycarbonyl-L-lysine N-carboxyanhydride (Z-L-lysine NCA, yield~70%) monomer. Then we applied the macromonomers and comomoner (GMA or NIPAm) to synthesize a series of the graft copolymers, poly(GMA)-graft-poly(Z-L-lysine) (PGMA-g-PZLLys) and poly(NIPAm)-co-poly(L-lysine) (PNIPAm-co-PLLys), and investigated the conformation of the graft copolymers. The graft copolymers were synthesized with different monomer ratios and different DP of the poly(Z-L-lysine) side chain to analyze secondary structure relationships. Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and both wide angle and small angle X-ray scattering spectroscopy (WAXS, SAXS) were employed to investigate the relationship between the microstructure and conformation of the graft copolymers PGMA-g-PZLLys and the different monomer ratios and side chain DP. In AFM images, both n8-G89 and n14-G43 (the graft copolymer containing 89% and 43% GMA units, and the macromonomer DP is 8 and 14, respectively) showed uniform rod-like structures, and FTIR spectra of the graft copolymers showed that the variations of α-helix and β-sheet secondary structures in the graft copolymers relate to the monomer ratios of the graft copolymers. However, the X-ray scattering patterns indicated that the graft copolymer confirmations were mainly dependent on the PZLLys side chain length, and these results were completely in accordance with the AFM images. The pH and temperature response properties of the graft copolymers PNIPAm-co-PLLys in aqueous solution were studied. The experimental results indicate PNIPAm-co-PLLys have coil-to-helix transitions from pH 6 to pH 12 at room temperature and form uniform nano-scale micelle-like dispersions in aqueous solution at pH 12. The graft copolymers also could form uniform and nano-scale micelle-like structures at 50oC in pH 6 buffer solution due to slightly polymer aggregation. In the second section of this study, the double hydrophilic graft copolymer PNIPAm-co-PLLys was conjugated with hydrophobic anti-tumor drug methotrexate (MTX) to prepare the amphiphilic polymer-drug conjugate, and the solution properties and micelle morphology of polymer-drug conjugate were studied by DLS, AFM, and TEM . The naturally crosslinker Genipin was used to cross-linked with PNIPAm-co-PLLys to obtain the shell cross-linked micelles, and MTX were encapsulated into shell cross-linked micelles. Then the entrapment efficiency and drug loading content of drug-loaded shell cross-linked micelles were evaluated by HPLC. The drug release profiles of MTX from the shell cross-linked micelles were preformed in pH 7.4 phosphate buffer solutions at 37oC, and the cumulative MTX release were about 90% in L15-N65 and 62~66% in L30-N70, respectively.

Topic Category 工學院 > 化學工程學系
工程學 > 化學工業
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