角膜新生血管可經由缺氧、發炎、感染、熱或化學損傷等所引起的病理狀況。角膜新生血管也是全球第四大致盲原因。造成角膜新生血管的主要原因之一是血管內皮生長因子 (VEGF) 與其受體 (VEGFR2) 結合導致的血管異常生長至無血管的角膜基質中。此外基質中增加累積的活性氧物質 (ROS) 也藉由引發血管新生途徑加速了角膜新生血管的進展和嚴重性。因此，開發一種用於抑制血管生成和減少活性氧物質的多功能藥物有其必要性。兒茶素 (Catechin, Ch) 是一種具有抗氧化、抗發炎和抗血管生成特性的多酚物質。然而，多酚的水溶性和穩定性差，導致其生物利用度低，從而限制了醫學應用性。在本研究中，通過將兒茶素在 210 °C下鍛燒，接著在鹼性條件下聚合一小時，生成靶向角膜新生血管的碳化聚兒茶素奈米粒子 (c-pCh)。此c-pCh表現出優異的抗血管生成作用，並且可通過增強兒茶素與VEGFR2的結合來有效緩解氧化應激依賴性的血管生成。此外，在經由角膜縫合引發新生血管的大鼠模型中，與單體兒茶素相比，c-pCh取得了更好的治療效果。本研究之結果顯示，c-pCh是角膜新生血管病理機制中，ROS介導新生血管治療之有效替代方案。

Corneal neovascularization (CNV), a pathological condition that is caused by hypoxia, inflammation, infection, thermal or chemical injury. CNV is also the fourth leading cause of blindness worldwide. One of the leading causes of CNV is the abnormal growth of blood vessels into the avascular corneal stroma caused by the vascular endothelial growth factor (VEGF) binding to its receptor VEGFR2. The increased accumulation of reactive oxidative species (ROS) in the stroma also accelerates the progression and severity of CNV by ROS-induced angiogenesis. As a result, it is essential to develop a multifunctional medicine for angiogenesis inhibition and ROS reduction. Catechin (Ch) is a polyphenolic substance with antioxidant, anti-inflammatory, and anti-angiogenesis properties. However, the poor water solubility and stability of polyphenols result in low bioavailability and thus limit its medical application. In this work, a carbonized-polycatechin (c-pCh) targeting CNV was generated by calcination of catechin (Ch) at 210 °C followed by polymerization under alkaline condition for one hour. The resultant c-pCh exhibited excellent anti-angiogenesis effect and can effectively alleviate oxidative stress-dependent angiogenesis by enhancing the binding between Ch and VEGFR2. Furthermore, the c-pCh achieved superior treatment effect compared to the monomeric catechin in the rat model of suture-induced corneal neovascularization. In summary, this study demonstrates that c-pCh is a promising alternative for the treatment of ROS-mediated neovascularization in corneal neovascularization pathogenesis.

中文摘要………………………………………………………………………………1
ABSTRACT………………………………………………………………………………2
謝誌………………………………………………………………………………3
Contents………………………………………………………………………………4
Chapter 1 INTRODUCTION………………………………………………………………………………6
1. Corneal neovascularization………………………………………………………………………………6
1.1 Pathological mechanism of CNV………………………………………………………………………………6
1.2 Current methods and dilemma for the treatment of CNV……………………………8
1.3 Literature review on CNV treatment………………………………………………………………………………9
1.3.1 Nanomaterials………………………………………………………………………………9
1.3.2 Graphene-based materials………………………………………………………………………………12
1.3.3 Polyphenol………………………………………………………………………………14
1.4 Research Objectives………………………………………………………………………………19
Chapter 2 EXPERIMENTAL METHODS………………………………………………………………………………22
2.1 Chemicals………………………………………………………………………………22
2.2 General techniques………………………………………………………………………………24
2.3 Synthesis of carbonized polycatechin (c-pCh)………………………………………………25
2.4 Cell lines and cell culture………………………………………………………………………………25
2.5 Anti-angiogenesis effect………………………………………………………………………………25
2.6 The mechanism of the inhibition effect of c-pCh on VEGF-induced angiogenesis………………………………………………………………………………27
2.7 Antioxidant efficacy of c-pCh………………………………………………………………………………28
2.8 In vivo study………………………………………………………………………………29
Chapter 3 RESULTS AND DISCUSSION………………………………………………………………………………32
3.1 Synthesis of carbonized polycatechin (c-pCh) at different temperatures.………………………………………………………………………………32
3.2 Anti-angiogenesis effects of c-pCh on endothelial cell proliferation, migration and tube formation.………………………………………………………………………………35
3.3 Antioxidant activity of c-pCh can attenuate ROS-dependent angiogenesis.………………………………………………………………………………38
3.4 In vivo angiogenesis inhibition by pCh-210 in CNV rat model. ………………………………………………………………………………39
Chapter 4 CONCLUSION………………………………………………………………………………41
REFERENCES………………………………………………………………………………42
Table………………………………………………………………………………54
Figures………………………………………………………………………………55
Abbreviations………………………………………………………………………………79

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