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研究生： 游有弘
You, You-Hong
論文名稱： 利用聚多巴胺修飾之星形金奈米粒子作為標靶性光熱/藥物傳遞載體應用於抗腫瘤及抗血管新生結合性治療
Polydopamine-coated gold nanostars as a tumor-targeted photothermal/drug delivery nanoplatforms for combined tumor- and neovascular- therapy
指導教授： 黃郁棻
Huang, Yu-Fen
口試委員: 張建文
Chang, Chien-Wen
胡尚秀
Hu, Shang-Hsiu
姜文軒
Chiang, Wen-Hsuan
學位類別： 碩士
Master
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2018
畢業學年度： 107
語文別： 英文
論文頁數： 70
中文關鍵詞： 金奈米星星 、聚多巴胺 、抗血管新生 、癌症治療 、藥物傳遞
外文關鍵詞： gold nanostar, polydopamine, antiangiogenesis, cancer therapy, drug delivery
相關次數： 點閱：3  下載：0 
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    • 腫瘤結合性治療廣泛地應用在生醫領域以及大幅度改善癌症治療效率，我們開發了多功能性聚多巴胺修飾之星形奈米粒子當作藥物載體 (NS-D@PPFA)，應用於標靶結合性治療。星形奈米粒子擁有高光熱轉換能力，可作為光熱試劑的角色。除此之外，聚多巴胺以及HS-PEG-FA的表面修飾，改善了星形奈米粒子在藥物載附及標靶性的能力。在細胞實驗中，NS-D@PPFA比起沒有標靶性的藥物載體更容易藉由受器所引導之胞吞作用進入細胞。此外，經由近紅外光雷射照射下，載體誘導的光熱效果及藥物控制釋放達到化學結合光熱治療的效果，此部分在MCF-7 (人類乳癌細胞)、MCF-7/ADR (抗藥性人類乳癌細胞)及HUVEC (人類臍帶內皮細胞)細胞上都有明顯毒殺的作用。相反地，結合性治療在NIH/3T3及HaCaT等正常細胞下則無明顯細胞毒性，顯示標靶性奈米材料在選擇性的優勢。除此之外，藥物載體對於血管增生因子VEGF有良好的親和力 (Kd = 2.68 × 10-10 M)，此數值相較於一般蛋白質高了約兩個級數。因此，藉由載體對於VEGF專一性吸附，抑制血管新生下游端訊號的活化。細胞實驗也證明在有藥物載體的條件下，可以有效抑制VEGF所誘導的血管新生途徑，同時達到抗腫瘤結合抗血管新生之效果。整體來說，此研究開發多功能藥物載體透過多樣結合性方法達到有效治療多重抗藥性腫瘤的效果。

    Cancer combination therapy can improve treatment efficacy and have been widely utilized in the biomedical field. In this study, we proposed a facile strategy to develop a multifunctional polydopamine coated gold nanostar as a chemodrug carrier (NS-D@PPFA) for cancer targeting and combination therapy. Gold nanostar (NS) shows high photothermal conversion efficiency due to a tip-enhanced plasmonic effect. The modification of polydopamine and folic acid (HS-PEG-FA) on NS surface also improves the drug loading efficiency and targeting capability. In vitro, NS-D@PPFA can be easily uptake by targeted breast cancer MCF-7 cells relative to non-targeted cells through a receptor-mediated endocytosis pathway. In combination with the photo-thermal effect induced by near infrared (NIR) laser irradiation, controlled payload release can be activated in response to both internal (acid) and external (photothermal) stimuli, leading to an efficient chemo-photothermal action against MCF-7 cells, drug-resistant MCF-7/ADR and Human Umbilical Vein Endothelial Cells (HUVEC). Conversely, cellular damage is less obvious in the cases of normal HaCaT (human skin keratinocytes) and NIH-3T3 cells (murine fibroblasts). In addition, payload-free NS@PPFA also exhibits high binding affinity (Kd = 2.68 × 10-10 M) toward vascular endothelial growth factor (VEGF-A165), which is at least two orders of magnitude stronger than that of high abundant plasma proteins such as human serum albumin. In vitro study further demonstrated that NS@PPFA can effectively inhibit the VEGF-A165-induced proliferation, migration and tube formation of HUVECs, resulting in additional therapeutic benefits in combating tumor via a simultaneous anti-angiogenic action in chemo-photothermal treatment. Overall, our “all-in-one” nanoplatform is highly promising for potential tumor therapy, allowing effective treatment against multidrug resistant cancers.

    Abstract I Chapter 1. Introduction 1 1.1 Nano-technology and biomedical application 1 1.1.1 Introduction of Nanomaterials 1 1.1.2 Nanocarriers 1 1.1.3 Stimuli-responsive nanocarriers 2 1.2 Cancer therapy and its application 5 1.2.1 Introduction of cancer 5 1.2.2 Chemo-photothermal therapy 6 1.2.3 Antiangiogenic therapy 8 1.2.4 Antitumor combined antiangiogenic therapy 10 1.3 Polydopamine and gold nanostar applied in cancer therapy 11 1.3.1 Gold nanostar 11 1.3.2 Polydopamine 12 1.3.3 The application of Au@PDA nanocomposites in drug delivery 14 1.4 Research motivation and purpose 15 Chapter 2. Experimental Method 17 2.1 Material and instrument 17 2.1.1 Experiential agent 17 2.1.2 Instrument 17 2.2 Synthesis and characterization of NS-D@PPFA 18 2.2.1 Synthesis of NS 18 2.2.2 Preparation of NS-D@P 18 2.2.3 Preparation of NS-D@PPFA 19 2.2.4 Characterization of NS-D@PPFA. 19 2.3 Properties of NS-D@PPFA in buffer solution 20 2.3.1 Long-termed stability of NS-D@PPFA 20 2.3.2 Photothermal effect of NS-D@PPFA 20 2.3.3 DOX release of NS-D@PPFA 20 2.4 The interaction of NS-D@PPFA toward MCF-7 cells 21 2.4.1 Cell culture 21 2.4.2 Cellular uptake of NS-D@PPFA 21 2.4.3 Intracellular DOX release of NS-D@PPFA 22 2.4.4 Cytotoxicity of NS-D@PPFA 22 2.4.5 The evaluation of cell recurrent 23 2.4.6 Cell apoptosis assay of NS-D@PPFA 23 2.5 The interaction of NS@PPFA toward HUVEC cells 24 2.5.1 Adsorption of VEGF on NS@PPFA 24 2.5.2 Adsorption of BSA on NS@PPFA 24 2.5.3 Proliferation assay of HUVEC cells 25 2.5.4 Migration assay of HUVEC cells 25 2.5.5 Tube formation assay of HUVEC cells 26 Chapter 3. Result and Discussion 27 3.1 Synthesis and characterization of NS-D@PPFA 27 3.1.1 Synthesis of NS-D@PPFA 27 3.1.2 Characterization of NS-D@PPFA 27 3.2 Properties of NS-D@PPFA in buffer solution 29 3.2.1 Photothermal effect of NS-D@PPFA 29 3.2.2 Drug release of NS-D@PPFA 30 3.3 The interaction of NS-D@PPFA toward breast cancer MCF-7 cells 31 3.3.1 Cellular uptake of NS-D@PPFA 31 3.3.2 Intracellular DOX release 32 3.3.3 Cytotoxicity of NS-D@PPFA 33 3.4 The interaction of NS-D@PPFA toward HUVEC cells 34 3.4.1 Cellular toxicity of NS-D@PPFA toward HUVEC cells 34 3.4.2 Antiangiogenic effect of NS-D@PPFA toward HUVEC cells 35 3.4.3 Binding affinity of NS@PPFA toward VEGF 36 Chapter 4. Conclusion 38 Figure Caption 39 Reference 64

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