雙親水端共聚物應用於治療銅中毒疾病;Poly(2-methacryloyloxyethyl phosphorylcholine-b-serinyl acrylate) Block Copolymer for the Treatment of Copper Poison

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题名:	雙親水端共聚物應用於治療銅中毒疾病;Poly(2-methacryloyloxyethyl phosphorylcholine-b-serinyl acrylate) Block Copolymer for the Treatment of Copper Poison
作者:	郭星昱;Kuo, Shing-Yu
贡献者:	生物醫學工程研究所
关键词:	重金屬中毒;螯合;金屬膠體;高分子膠體;高分子;微胞;heavy metal poisoning;poly(2-methacryloyloxyethyl phosphorylcholine);poly(L-serinyl acrylate);chelation;polymeric metal colloids
日期:	2019-07-25
上传时间:	2019-09-03 14:35:41 (UTC+8)
出版者:	國立中央大學
摘要:	重金屬汙染已經對人類的健康產生嚴重的威脅。銅是人體必需的金屬元素之一，然而過量地攝取銅離子會引發嚴重的副作用。胺基酸已經被應用於人體內的銅離子移除治療，此外聚丙烯醯氧絲胺酸酯(Poly(serine acrylate, PserA))已被報導可作為螯合劑與銅離子螯合，然而PserA與銅離子螯合後會形成沉澱並且提升生物毒性。本研究利用可逆加成斷裂鏈轉移聚合法(Reversible Addition-Fragmentation chain Transfer polymerization, RAFT)，將PserA與聚2-甲基丙烯醯氧乙基磷酸膽鹼(Poly(2-methacryloyloxyethyl phosphorylcholine), PMPC)組成線性共聚物(PMPC-b-PserA)，PMPC可有效增加PMPC-b-PserA與銅離子螯合後的溶解度，同時降低生物毒性。我們使用核磁共振光譜來檢測共聚物上的氫原子與碳原子，利用傅立葉轉換紅外光譜鑑定磷酸基、胺基與羧酸基的訊號，使用質譜法檢測丙烯醯氧絲胺酸酯的分子量以及膠體滲透層析儀量測共聚物的分子量。經由紫外光-可見光譜儀證實在pH值為7的條件下，聚丙烯醯氧絲胺酸酯與銅離子形成金屬膠體，此外我們以動態光散射儀量測不同聚合度的PMPC-b-PserA、環境pH值、離子強度與血清對於金屬膠體粒徑的影響。並且運用穿透式電子顯微鏡拍攝金屬膠體的形狀。最後藉由老鼠纖維母細胞(NIH/3T3)測試PMPC-b-PserA的細胞毒性與解毒效果。結果顯示PMPC-b-PserA具有可忽略的細胞毒性且有效的提升細胞的存活率於含有銅離子的環境，溶血實驗中也顯示了PMPC-b-PserA能夠有效降低銅離子引發的溶血現象。本研究提出了一種全新移除重金屬離子的方式，對於治療重金屬中毒做出了貢獻。 ;The issue of heavy metal poisoning is very much concerned as it cause major risks for human health. Although copper (Cu) an essential element in the human body, excessive intake can have adverse effects on the systems in the human body. Poly amino acid was evaluated for possible use as an chelating agent in the treatment of metal intoxication in human body. Poly(serinyl acrylate) (PserA) were developed for its chelation with copper(II) ions. However, the precipitation formed will increase the toxicity level. Herein, we employ 2-methacryloyloxyethyl phosphorylcholine (MPC) to avoid precipitation and form metal colloids to decrease toxicity. We report a robust apporach to synthesize the double hydrophilic block copolymers(DHBCs) of PserA and PMPC via reversible addition-fragmentation chain transfer polymerization (RAFT). A variety of techniques were applied to confirm the synthesis and structure of this copolymer including 1H nuclear magnetic resonance (NMR), 13C NMR, fourier-transform infrared spectroscopy (FTIR), mass spectra (MS) and gel permeation chromatography (GPC). In addition, the chelating PMPC-b-PserA loaded to copper ions at pH = 7.2 were indicated by ultraviolet–visible spectroscopy(UV-vis). Dynamic light scattering (DLS) was applied to correlate between the Cu2+/serA ratio and the size of metal colloids at pH=7.2. We also studied influence of degree of polymerization(DP), pH effect, ionic strength and serum. Transmission electron microscopy (TEM) was also operated to take metal colloid′s image. Finally, the double hydrophilic block copolymers(DHBCs) was tested on NIH-3T3 fibroblasts normal cells to study the detoxification effect. The double hydrophilic block copolymers possesses good biocompatibility to remove excess copper(II) ions and increase the cell viability in vitro. Hemolysis assay demonstrates that copolymer drastically decreases red blood cell(RBC) hemolysis from copper(II) in vitro. This strategy provides another treatment approach for heavy metal poisoning.
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