市售肝素 (heparin) 為目前最為普遍使用的抗凝血劑，然而其容易產生副作用，以往減輕肝素副作用的方法為將其進行結構改良或是合成類似物來取代，但合成步驟極為繁複且昂貴。許多研究指出，海藻萃取出的生物活性分子有許多應用，包括抗癌、抗腫瘤、抗病毒，其中硫酸多醣 (sulfated polysaccharides) 可作為抗凝血劑。由於天然的硫酸多醣不易萃取且成本極高，費時且獲得的產率低，近年來有諸多利用硫化物 (sulfur compounds) 將一般多醣硫酸化後作為抗凝血劑應用。其中，海藻酸鈉 (alginate) 為一種萃取於褐藻的多醣，單元結構類似肝素且成本低。為了突破硫酸化後海藻多醣分子不穩定性以及無顯著性的抗凝血效果，因此本研究欲將海藻酸鈉及亞硫酸銨 (ammonium sulfite, (NH4)2SO3) 混和後，經由簡單一步 (one-step) 乾燒合成硫酸化海藻酸鈉碳奈米材料。在165 °C的條件之下，我們成功製備出硫酸化之海藻酸鈉碳奈米線 (sulfated@alginate-carbon nanowires, CNWsAlg@SOx)。實驗證實CNWsAlg@SOx能夠與凝血酶 (thrombin) 結合，達到延長凝血酶凝固時間 (thrombin clotting time, TCT)，且效果比海藻酸鈉高100倍以上。於溶血實驗 (hemolysis assay) 結果顯示CNWsAlg@SOx不會造成紅血球溶血，使其具有成為注射型抗凝血奈米材料潛力。此外，鼠尾出血時間試驗 (tail bleeding time) 顯示其抗凝血時間比海藻酸鈉高6倍以上，證明此奈米抗凝血劑能成功應用於活體試驗中，且達到良好效果。未來將測試其他種藻類與不同硫化物一步乾燒製成其他奈米抗凝血劑。

Heparin is the most commonly used commercial anticoagulant; however, it can potentially cause very serious side effects. Structural modification of heparin or development of heparin analogs are common methods used to reduce its side effects. These methods often involve complex synthesis procedures and expensive chemicals. Studies suggest that extracts of marine algae are rich in bioactive chemicals with many properties including anticancer, antitumor and antivirus. Sulfated algal polysaccharides, in particular, are known to have anticoagulation properties. However, extraction of such polysaccharides are time consuming and expensive, which bring about the need for chemically sulfating polysaccharides with sulfur compounds. Alginate, a non-sulfated polysaccharide, is a popular choice due to its structural similarity to heparin and low cost. Unfortunately, its low bio-stability and less than satisfactory anticoagulation efficiency limits its application. In this research, we hope to improve the anticoagulation efficiency of alginate by nanonizing its structure and sulfating its functional groups. We successfully synthesized sulfated alginate carbon nanowires (CNWsAlg@SOx) by heat treatment of alginate with ammonium sulfate at 165 °C. We have demonstrated that the CNWsAlg@SOx can inhibit thrombin activity through electrostatic interaction. Thrombin clotting time (TCT) assay revealed our CNWsAlg@SOx has 100-fold longer TCT compared to its precursor. Its low hemolytic activity demonstrated its potential for intravenous administration. Tail bleeding assay revealed that our material is 6-fold more efficient in vivo compared to its alginate precursor. We will extend our research to synthesize carbon nanomaterials by varying the carbon source and sulfur compounds to develop more efficient anticoagulants.

中文摘要 I
英文摘要 II
Contents III
Figure of contents IV
Table of contents V
1. Introduction 1
1-1 Blood coagulation and anticoagulation methods 1
1-2 Polysaccharides from marine algae for biomedical applications 2
1-2-1 Polysaccharides extracted from marine algae 2
1-2-2 Marine algae for antioxidant application 3
1-2-3 Marine algae for anticancer application 3
1-2-4 Marine algae for antiviral application 4
1-2-5 Marine algae for anticoagulation application 4
1-3 Sulfated polysaccharides for anticoagulation application 5
1-4 Applications of nanomedicines as anticoagulants 7
1-4-1 Inorganic nano-anticoagulants 8
1-4-2 Organic nano-anticoagulants 8
1-4-3 Carbon nanomaterials as anticoagulants 9
1-5 Carbon nanowires 9
1-5-1 Introductions of carbon nanowires 9
1-5-2 Synthesis of carbon nanowires 10
1-5-3 Application of carbon nanowires 11
1-6 Motivation Reasearch 11
2. Experimental 13
2-1 Materials 13
2-2 Instruments 13
2-3 Synthesis of alginate- and sulfated alginate-carbon nanomaterials 14
2-4 FT-IR measurements 15
2-5 Measurement of degree of sulfation 15
2-6 Thrombin clotting time (TCT) assay 15
2-7 PT and aPTT assay 16
2-8 Thromboelastography 16
2-9 Determination of binding constant 17
2-10 Hemolysis assays 17
2-11 Determination of rat-tail bleeding time 18
3. Results and discussion 18
3-1 Synthesis of carbon nanomaterials from alginate and alginate-sulfite mixture 19
3-2 Characterization of CNMsAlg@SOx -165 22
3-3 Mechanism of nanowire formation in CNMsAlg@SOx-165 23
3-4 Anticoagulation properties of CNMsAlg@SOx 25
3-5 Prothrombin time and activated partial thromboplastin time 27
3-6 Thromboelastography 28
3-7 Hemolysis assays 28
3-8 In vivo rat-tail bleeding assay 28
4. Conclusion 30
Figures and tables 31
References 60

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