新型磷脂聚合物微胞於藥物輸送之應用;Novel Phospholipid Polymeric Micelle for Drug Delivery Application

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題名:	新型磷脂聚合物微胞於藥物輸送之應用;Novel Phospholipid Polymeric Micelle for Drug Delivery Application
作者:	沐為力;Muhammad, Metwally Ezzat Metwally
貢獻者:	生物醫學工程研究所
關鍵詞:	磷脂;聚合膠束;藥物遞送;Phospholipid;polymeric micelles;drug delivery;Curcumin
日期:	2016-11-23
上傳時間:	2017-01-23 16:14:14 (UTC+8)
出版者:	國立中央大學
摘要:	研究上微胞廣泛應用在藥物方面在於其有良好的穩定性，可增強水溶性藥物在人體中的溶解度，以及增強水溶性藥物在正確療程中，其有效劑量能夠釋放在正確的時間及地點。因此，新型的雙離子高分子中的親水疏水性結構-可逆之膽鹼磷酸鹽(choline phosphate,CP)和長烷基鏈將在本研究中被陳述。在本研究中，我們合成2-{2(Methacryloyloxy)ethyldimethylammonium}ethyl n-octyl phosphate (MOP)單體，爾後再透過reversible addition–fragmentation chain transfer (RAFT) polymerization聚合形成高分子。此新型高分子提供仿生性質之均聚物，具有疏水端之核仁以及親水端之CP外殼將會在水溶液中自組裝形成微胞結構。我們利用核磁共振儀(1H nuclear magnetic resonance,NMR)、核磁共振儀(31P nuclear magnetic resonance,NMR) 、質譜儀(mass spectra,MS)來鑑定其微胞結構。透過螢光光譜用於獲得臨界微胞濃度(CMC)，利用芘為探針在製備微胞之水溶液中測得臨界微胞濃度(CMC)。使用光動態散射儀(dynamic light scattering,DLS) 、原子力顯微鏡atomic force microscopy (AFM)和transmission electron microscopy (TEM).來鑑定其微胞大小，分布狀況以及其形狀。使用DLS測量ζ-potential values來測試微胞之穩定性。結果顯示，此新型微胞在200-300 nm時展現了非常低的微胞濃度:47 mg/L，本研究採用薑黃素與微胞作用形成一新型抗癌藥物，結果意外顯示，PMOP微胞可有效地增強薑黃素枝溶解度，當濃度為5 mg/mL時，溶解度可增強1.78×〖10〗^3倍；當濃度為50mg/ml時，溶解度可增強5.51×〖10〗^3倍。除此之外， NH3T3以及BFTC-905膀胱癌細胞將會使用在細胞毒性測試實驗中。而此微胞在濃度為50 mg/mL中仍具有相當良好之細胞生物存活率。本研究顯示當微胞負載薑黃素可降低癌症細胞之存活率，使微胞形成有潛力之藥物載體。此新型脂質微胞將為廣泛之生物醫學應用建立新的平台。關鍵字:磷脂質、高分子微胞、藥物輸送、薑黃素 ;The emergence of micelles in pharmaceutical applications are widely studied due to their stability, their ability to enhance solubility of the water-insoluble drugs and effectively control the release of active ingredients in a way of right medication, right time, right place, and right dose. Herein, a new zwitterionic polymer based on an amphiphilic structure of a reverse choline phosphate (CP) and long alkyl chain was described in this work. 2- {2(Methacryloyloxy)ethyldimethylammonium}ethyl n-octyl phosphate (MOP) monomer was synthesized and polymerized via reversible addition–fragmentation chain transfer (RAFT) polymerization. The new polymer affords new biomimetic homopolymer that can self-assemble to form micelle structure exhibiting a hydrophobic core and hydrophilic CP shell in aqueous media. A variety of techniques are applied to confirm the synthesis and structure of the new homopolymer micelles including 1H nuclear magnetic resonance (NMR), 31P NMR, and mass spectra (MS). Fluorescence spectroscopy was applied to obtain the critical micelle concentration (CMC) of the prepared micelles in aqueous media using pyrene as probe. The micelle size, size distribution and shape were confirmed by dynamic light scattering (DLS), atomic force microscopy (AFM), and transmission electron microscopy (TEM). The micelle stability was achieved by measuring ζ-potential values using DLS measurements. The results showed that the new micelles possess a very low CMC value of about 47 mg/L while the micelle size was as high as 200-300 nm. The anticancer drug - curcumin – was incorporated to the formed micelles in order to study the amphiphilic properties and in vitro release behavior. The results surprisingly indicated that the pMOP micelles can efficiently enhance the solubility of curcumin to 1.78 ×103 and 5.51×103 times when the pMOP concentrations were 5 mg/mL and 50 mg/mL, respectively. Additionally, the cytotoxicity of the blank micelles and Cur-loaded micelles are investigated on both NIH-3T3 fibroblasts normal cells and BFTC-905 bladder cancer cells to study the cell viability in the two cases. The blank micelles exhibited an excellent biocompatibility indicating its potential use as delivery systems even at very high concentration of 50 mg/mL. While the curcumin-loaded micelles have much better effect in reducing the cancer cell viability which makes the new micelle as a promising carrier for the delivery of poorly soluble drugs. The versatile new phospholipid micelle will establish new platforms for a wide range of biomedical applications.
顯示於類別:	[生物醫學工程研究所 ] 博碩士論文

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