血管阻塞、硬化或血管內壁損傷以致的血栓形成容易引發各類心血管疾病(cardiovascular diseases, CVD)，如肺栓塞、腦中風、缺血性潰傷等。溶栓藥物的使用為目前臨床最常用的手段，而溶栓後的發炎環境易使血栓再生成，需搭配抗凝血劑以及抗血小板藥物來協同治療，避免栓塞再次生成。多數溶栓藥物的臨床應用受到出血副作用和半衰期短的限制，因此本研究將利用褐藻醣膠(fucoidan, Fu)標靶血栓的能力將血栓溶解酵素蚓激酶(lumbrokinase, LK)標靶遞送至血栓位置，以改善此問題。抗血小板藥物多為疏水性小分子，且半衰期短，因此本研究利用羧甲基-β-環糊精(carboxymethyl-β-cyclodextrin sodium salt, CMCD)的疏水孔洞作為抗血小板分子白藜蘆醇(resveratrol, RES)之載體，以提高RES水溶性及生物利用性，並進一步利用精胺酸乙基醚(L-arginine ethyl ester dihydrochloride, Arg)的改質來增加RES的包覆率及緩釋能力。透過FTIR與1H NMR確認Arg於CMCD的接枝率約為34.93%。以此RES@CMCD-Arg複合物與Fu及魚精蛋白(protamine, Prot)以正負電自組裝製備奈米粒子，並將LK包覆其中，即Prot/RES@CMCD-Arg/LK/Fu NPs。此奈米粒子粒徑為148.6 ± 1.06 nm，表面帶負電(-19.9 ± 1.20 mV)，並可以分散於穩定生理環境中。在IVIS光譜成像中證明此奈米粒子可以藉由表面之Fu來與血栓結合。體外釋放與血栓溶解分析證明此奈米劑型可以有效釋放出具活性之LK，並於7 h後溶解約76%的血栓，此外，此奈米粒子可以降低71.3%之TRAP-6所誘導的血小板聚集。此結合標靶遞送與協同治療之奈米劑型具有應用於溶栓治療之潛力。

　　Thrombosis caused by vascular obstruction, sclerosis, or vascular injury can easily lead to various cardiovascular diseases (CVD), such as pulmonary thrombosis, stroke, and ischemic ulcer. Thrombolytic agents are currently the most commonly used clinical method, but the inflammatory environment after thrombolysis is easy to cause thrombosis regeneration, so anticoagulants and antiplatelet drugs must be used in conjunction with treatment to prevent re-occlusion. Most thrombolytic agents are limited in clinical use by their side effects of bleeding and short half-life. Therefore, this study will aims to use fucoidan (Fu) to target thrombus and deliver the thrombolytic enzyme lumbrokinase (LK) to the thrombus location to improve this problem. Most antiplatelet drugs are hydrophobic small molecules and short half-life, so this study uses the hydrophobic cavity of carboxymethyl-β-cyclodextrin sodium salt (CMCD) as a carrier for the antiplatelet molecule resveratrol (RES) to improve the water solubility and bioavailability of RES, and further uses the modification of arginine (Arg) to increase the encapsulation rate and slow release ability of RES. The grafting rate of Arg on CMCD was confirmed to be about 34.93% by FTIR and 1H NMR. The RES@CMCD-Arg complex is self-assembled with Fu and protamine (protamine, Prot) to prepare nanoparticles (NPs), and LK is coated in them, that is, Prot/RES@CMCD-Arg/LK/Fu NPs. The Prot/RES@CMCD-Arg/LK/Fu NPs had a size of 148.6 ± 1.06 nm, the surface is negatively charged (-19.9 ± 1.20 mV), and were stable in a physiological environment. In IVIS spectral imaging showed that Prot/RES@CMCD-Arg/LK/Fu NPs can bind to thrombus through Fu. In vitro release and thrombolysis analyses proved that the NPs had good thrombolytic activity and could effectively release the LK, and dissolve about 76% of the thrombus after 7 hours. In addition, the NPs can reduce the platelet aggregation induced by TRAP-6 by 71.3%. This nanocarriers form combined with target delivery and synergistic therapy has the potential to be applied to thrombolytic therapy.

摘要 I
Abtract II
目錄 III
表次 VI
圖次 VII
縮寫表 IX
1. 前言 1
2. 文獻回顧 3
2.1. 心血管疾病 3
2.1.1. 冠狀動脈疾病 3
2.1.2. 周邊血管疾病 3
2.1.3. 血栓形成 4
2.1.4. 血管阻塞的臨床治療 5
2.2. 血栓標靶 5
2.2.1. 褐藻醣膠 5
2.2.2. 褐藻醣膠與P-selectin之結合性 6
2.3. 纖維蛋白酶用於血栓溶解 6
2.3.1. 蚓激酶 6
2.3.2. 生理活性 7
2.3.3. 溶解血栓 8
2.4. 協同治療與血栓溶解的應用 8
2.4.1. 抗血小板藥物 8
2.4.2. 氣體治療用於血管內皮再生 10
2.4.3. 抗凝血劑 11
2.5. 奈米載體遞送技術 11
2.5.1. 電荷自組裝奈米載體 12
2.5.2. 分子生物及傳遞之材料 12
2.5.3. 疏水藥物遞送 13
3. 實驗材料 14
3.1. 細胞株 14
3.2. 動物 14
3.3. 實驗藥品 14
3.4. 儀器設備 15
4. 實驗架構 17
5. 實驗方法 19
5.1. 樣品製備 19
5.1.1. β-環糊精裝載白藜蘆醇(RES@CD) 19
5.1.2. 合成羧甲基-β-環糊精-精胺酸乙基醚(CMCD-Arg) 19
5.1.3. 羧甲基-β-環糊精-精胺酸乙基醚裝載白藜蘆醇(RES@CMCD-Arg) 19
5.1.4. NPs之合成 19
5.1.5. BR標記蚓激酶 20
5.1.6. BR標記褐藻醣膠 20
5.2. 基本性質分析 20
5.2.1. 粒徑與界面電位分析電位 20
5.2.2. 穿透式電子顯微鏡分析 20
5.2.3. FTIR化學結構分析 21
5.2.4. 核磁共振光譜分析(NMR) 21
5.2.5. RES裝載量分析 21
5.2.6. 藥物包覆率分析 22
5.2.6.1. RES包覆率分析 22
5.2.6.2. LK包覆率分析 22
5.3. 模擬環境刺激敏感性與穩定性質分析 22
5.4. NPs之LK與RES@CMCD-Arg釋放試驗 22
5.5. EA.hy926細胞之實驗 22
5.5.1. EA.hy926細胞株之培養 23
5.5.2. NPs對EA.hy926細胞之相容性 23
5.5.3. RES在EA.hy926細胞之攝取 23
5.5.4. NPs在EA.hy926細胞之攝取 23
5.6. 體外血栓親和性測試 24
5.7. 血栓溶解分析 24
5.8. 血小板功能測試 24
5.9. 統計分析 25
6. 結果與討論 26
6.1. RES@CMCD-Arg / RES@CD之製備與特性分析 26
6.1.1. β-環糊精裝載白藜蘆醇(RES@CD) 26
6.1.2. 羧甲基-β-環糊精-精胺酸乙基醚(CMCD-Arg) 27
6.1.3. 羧甲基-β-環糊精-精胺酸乙基醚裝載白藜蘆醇(RES@CMCD-Arg) 27
6.2. 基本性質分析 27
6.2.1. NPs之粒徑、界面電位與型態分析 27
6.2.2. NPs之FTIR分析結果 28
6.3. NPs之模擬環境刺激敏感性與穩定性質分析 29
6.4. NPs之LK與RES@CMCD-Arg釋放試驗 30
6.5. EA.hy926細胞之實驗 31
6.5.1. NPs對EA.hy926細胞之相容性 31
6.5.2. RES在EA.hy926細胞之攝取 32
6.5.3. NPs在EA.hy926細胞之攝取 33
6.6. 體外血栓親和性測試 33
6.7. 血栓溶解分析 34
6.8. 血小板功能測試 35
7. 結論 37
8. 參考資料 38
9. 表 59
10.圖 61
11.附錄 98

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