雙親水端共聚物應用於治療銅中毒疾病

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姓名

郭星昱(Shing-Yu Kuo) 查詢紙本館藏

畢業系所

生物醫學工程研究所

論文名稱

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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摘要(中)

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。

摘要(英)

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.

關鍵字(中)

★ 重金屬中毒
★ 螯合
★ 金屬膠體
★ 高分子膠體
★ 高分子
★ 微胞

關鍵字(英)

★ heavy metal poisoning
★ poly(2-methacryloyloxyethyl phosphorylcholine)
★ poly(L-serinyl acrylate)
★ chelation
★ polymeric metal colloids

論文目次

中文摘要 i
Abstractiii
致謝 v
目錄 viii
圖目錄 xv
表目錄 xx
第一章: 文獻回顧 1
1.1 重金屬汙染 1
1.2 金屬銅 1
1.3 銅在人體中扮演的角色 2
1.4 銅中毒疾病的介紹 2
1.4.1 急性銅中毒 3
1.4.2 慢性銅中毒 3
1.5 當前重金屬中毒的治療方法 4
1.5.1抑制銅的吸收 4
1.5.2移除體內過量的銅 4
第二章 : 介紹 6
2.1 高分子 6
2.1.1單離子高分子 6
2.1.2雙離子高分子 7
2.1.2.1 polyampholytes 8
2.1.2.2 polybetaines 9
2.1.2.2.1 Phosphobetaine 10
2.1.2.2.2 胺基酸 12
2.2雙親水端嵌段共聚物 14
2.3 自由基反應 15
2.3.1 可逆加成-斷裂鏈轉移聚合 17
2.3.2 可逆加成-斷裂鏈轉移聚合的反應機制 19
2.3.3 可逆加成-斷裂鏈轉移試劑 20
2.3.4 可逆加成-斷裂鏈轉移試劑的選擇 22
2.4奈米科技應用於生物體的螯合劑輸送 23
2.4.1 奈米粒子 23
2.4.2微胞 25
第三章 : 研究目的 27
第四章 : 材料與方法 28
4.1. 材料 28
4.2. 方法 30
實驗架構與流程 30
4.2.2 合成Poly(2-methacryloyloxyethyl phosphorylcholine) 33
4.2.3 合成Poly(Serinyl acrylate) 34
4.2.4 合成Poly(2-methacryloyloxyethyl phosphorylcholine-b-Pserinyl acrylate) 35
4.2.5 PMPCm-b-PserAn滴定曲線 36
4.2.6 PMPC55-b-PserA50螯合銅測試 36
4.2.7改變銅的濃度對於金屬膠束大小的影響 36
4.2.8改變PMPC55-b-PserA50的濃度對於金屬膠束大小的影響 36
4.2.9改變PMPCm聚合度對於金屬膠束大小的影響 37
4.2.10改變PserAn聚合度對於金屬膠體大小的影響 37
4.2.11錯合物濃度對於金屬膠束大小的影響 38
4.2.12離子強度對於金屬膠束大小的影響 38
4.2.13pH值對於金屬膠體大小的影響 38
4.2.14金屬膠體在DMEM+10% FBS中的穩定度 39
4.2.15穿透式電子顯微鏡下的金屬膠體 39
4.2.16NIH/3T3細胞培養 40
4.2.16.1 PMPC55-b-PserA50生物相容性測試 42
4.2.16.2相同莫爾濃度下聚合度對於生物相容性的影響 43
4.2.16.3相同莫爾濃度下高分子解毒效果測試 43
4.2.16.4相同重量下聚合度對於生物相容性的影響 43
4.2.16.5相同重量下高分子解毒效果測試 43
4.2.17高分子的溶血測試 44
4.2.18高分子抑制溶血的測試 44
第五章 : 結果與討論 45
5.1 serA單體鑑定 45
5.1.1 serA的核磁共振氫譜. 45
5.1.2 serA的核磁共振碳譜. 46
5.1.3 serA的傅里葉轉換紅外光譜 47
5.1.4 serA的質譜圖 48
5.2高分子合成鑑定 49
5.2.1核磁共振氫譜分析高分子 49
5.2.2核磁共振碳譜分析高分子 52
5.2.3 凝膠滲透層析儀分析高分子 55
5.2.4傅里葉轉換紅外光譜儀分析高分子 59
5.2.5高分子的轉化率、聚合度與產率 60
5.3 PMPCm-b-PserAn的酸鹼滴定 61
5.3.1修飾前後對於L-絲胺酸等電點的影響 61
5.4 PMPC55-b-PserA50螯合銅測試 64
5.4.1PMPC與銅之間的交互作用 65
5.4.2PMPC55-b-PserA50與銅之間的交互作用 66
5.5濃度對於粒徑的影響 67
5.5.1改變銅的濃度對於金屬膠體大小的影響 67
5.4.2 PMPC55-b-PserA50的濃度對於金屬膠體大小的影響 68
5.4.3改變PMPCm聚合度對於金屬膠體大小的影響 69
5.4.4改變PserAn聚合度對於金屬膠體大小的影響 70
5.4.5錯合物濃度對於金屬膠體大小的影響 71
5.5環境對於金屬膠體大小的影響 72
5.5.1離子強度對於金屬膠體大小的影響 73
5.5.2 pH值對於金屬膠體大小的影響 74
5.5.3金屬膠體在DMEM中的穩定度 76
5.6穿透式電子顯微鏡下的金屬膠體 77
5.7 小角度X光散射 (SAXS)判斷金屬膠體的形狀與尺寸 80
5.7.1 小角度X光散射 (SAXS)判斷金屬膠體的形狀 80
5.7.2 小角度X光散射 (SAXS)判斷金屬膠體的尺寸 82
5.8 生物相容性與解毒效果測試 83
5.8.1 硫酸銅對於生物毒性 83
5.8.2 PMPC55-b-PserA50對於細胞存活率的影響 84
5.8.2 PMPC55-b-PserA50的最佳治療濃度 85
5.8.3相同莫爾濃度下高分子的生物相容性與解毒效果 86
5.8.3.1改變PMPC聚合度對於細胞存活率的影響與解毒效果 87
5.8.3.2改變PserA聚合度對於細胞存活率的影響與解毒效果 90
5.8.4相同重量濃度下高分子的細胞存活率 92
5.8.4.1改變PMPC聚合度對於細胞存活率的影響與解毒效果 92
5.8.4.2改變PserA聚合度對於細胞存活率的影響與解毒效果 94
5.9溶血實驗 96
5.9.1高分子的溶血實驗 96
5.9.2高分子抑制溶血的測試 97
第六章：結論 98
參考文獻 99

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指導教授

黃俊仁(Chun-Jen Huang)

審核日期

2019-7-25

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