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系統識別號 U0026-0909201717311600
論文名稱(中文) 阿黴素/氧化矽碳空心球結合化學-光熱療法對肝癌細胞之效應評估
論文名稱(英文) Chemo-photothermal effects of doxorubicin/silica-carbon hollow spheres on liver cancer
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 105
學期 2
出版年 106
研究生(中文) 陳英齊
研究生(英文) Ying-Chi Chen
學號 P88991157
學位類別 博士
語文別 英文
論文頁數 71頁
口試委員 指導教授-張憲彰
口試委員-邱文泰
口試委員-林弘萍
口試委員-丁信智
口試委員-吳炳慶
口試委員-陳密
中文關鍵字 化學-光熱療法  肝癌  刀豆素A  氧化矽碳空心球  阿黴素 
英文關鍵字 chemo-photothermal therapy  liver cancer  Concanavalin A  silica-carbon hollow spheres  doxorubicin 
學科別分類
中文摘要 肝細胞癌(Hepatocellular carcinoma, HCC) 主要是由B型肝炎所引起,是最為常見且死亡率高的癌症。截至目前,傳統肝癌治療方式仍無法根除癌症,它仍存在許多的問題,包含:低存活率、全身性副作用、高醫療成本等。本研究希望結合化學治療與光熱治療,提供一種新穎的癌症治療方式。因為化學-光熱療法具有協同的效果,比起單獨使用化學療法或光熱療法來得有效,它具有優越的靶向與破壞癌細胞的能力。刀豆素A (Concanavalin A, ConA)分離自傑克豆(Jack bean),是一種外源凝集素(Lectins),當它結合到細胞膜表面上含甘露醣及葡萄糖的醣蛋白,會直接引發肝癌細胞的自噬反應與間接的活化T細胞,此雙重作用可以抑制腫瘤細胞的生長。而肝癌細胞表面的醣蛋白會異常過度表現,使得肝癌細胞具有相對大量的糖蛋白受體。因此,刀豆素A可以大量的結合到肝癌細胞,達到標靶治療的效果。氧化矽碳空心球(Silica-carbon hollow spheres, SCHSs)經由表面活化法合成,其高孔洞率(孔徑~11 nm)的表面能增加所需藥物的負載量。且氧化矽碳空心球是一種具有良好光熱效應的材料,可在808 nm的近紅外光(Near-infrared, NIR)雷射照射下,通過加熱來破壞目標癌細胞。
本論文目的是欲探討化學-光熱療法對肝癌細胞之效應。總共有兩個部份的研究包含於本論文中:第一個部分欲確認刀豆素A與氧化矽碳空心球之複合物(ConA-SCHSs)的光熱治療(Photothermal therapy, PTT)效果;第二個部分是基於第一個部分的研究結果,欲進一步的探討氧化矽碳空心球結合抗癌藥物,在光熱與藥物傳遞系統下對於肝癌細胞的影響。
論文第一部分的研究結果顯示,利用刀豆素A與氧化矽碳空心球之複合物,結合近紅外光對肝癌細胞進行熱消融治療。經由Hoechst 33342染色測定證實ConA-SCHSs的細胞毒性,即使以高濃度的ConA-SCHSs (500:200 g/mL)與細胞培養24小時,ConA-SCHSs對正常肝細胞(NeHepLxHT)和肝癌細胞(ML-1和Huh-7)都沒有明顯的細胞毒性傷害,具有良好的生物相容性。此外,通過流式細胞儀的分析與共軛焦顯微鏡的影像,我們發現刀豆素A-氧化矽碳空心球之複合物(ConA-SCHSs=250:100 g/mL or 125:50 g/mL)對肝癌細胞的結合率遠高於正常肝細胞(約2~6倍)。大部分ConA-FITC-SCHS結合在細胞膜上,只有少部分會進入細胞質。當肝癌細胞和刀豆素A-氧化矽碳空心球之複合物培養,通過隨後的近紅外光(0.72 W/cm2)照射,肝癌細胞更容易被殺死。結果顯示,ConA-SCHSs之複合物可以增強與高度表達刀豆素A受體的肝癌細胞相互作用,從而成為一種對肝癌治療有效的光熱治療方法(癌細胞死亡率可達100%)。
論文的第二個部分欲評估阿黴素/氧化矽碳空心球結合化學-光熱療法對肝癌細胞之效應。利用真空加熱的方式使抗癌藥物-阿黴素(Doxorubicin, DOX)負載到氧化矽碳空心球上,經由此方法可以實現高封裝率(~90%)。此外,近紅外光雷射的照射,應能促進阿黴素從氧化矽碳空心球釋放並增加細胞膜對抗癌藥物的通透性,從而提高阿黴素的抗癌效率。我們發現氧化矽碳空心球具有高度的發熱能力(~55°C)與對酸鹼值(pH)產生響應的藥物傳遞能力。當pH值從7.4變化至5.5,能增加DOX的釋放率(~35%)。利用活死細胞測定法(Live-dead cell assay)計算相對細胞存活率,證實在僅利用氧化矽碳空心球的條件下,施加808 nm近紅外光(9 W/cm2, 3分鐘)照射,細胞的致死率可達65%,然而使用阿黴素/氧化矽碳空心球的條件下,通過近紅外光照射可以達到更高的細胞致死率(~95%)。
最後,目前的研究結果表明,通過近紅外光照射誘導的阿黴素/氧化矽碳空心球具有高度的癌細胞致死效率,證明阿黴素/氧化矽碳空心球是潛在的化療與光熱協同治療工具,此平台可以被運用於腫瘤治療。
英文摘要 Hepatocellular carcinoma (HCC), the most common cancers in the world, is mainly causes by HBV infection. So far, HCC still can’t be eradicated by traditional liver cancer treatments. A lot of unsolved problems still existed, including low survival rate, systemic side effects, high medical costs and other issues. In this study, we aimed to combine chemotherapy with photothermal therapy to provide a novel approach for cancer treatment. Chemo-photothermal therapy (CPT), which exhibits synergistic effects, is much more effective than either treatment alone, because of its superior ability for targeting and destroying cancer cells. Concanavalin A (ConA) is one of the lectins (carbohydrate-binding protein) which isolated from the jack bean (Canavalia ensiformis). Con A can cause both autophagic induction on hepatocytes and immunomodulation on T cells to inhibit tumor growth due to the mannose/glucose-specific binding on cell membrane. Aberrant overexpression of glycoprotein receptors have been reported in liver cancer cells. Thus, relatively vast quantities of ConA can bind to the glycoprotein receptors located on HCC to achieve the effect of targeted therapy. Silica-carbon hollow spheres (SCHSs) were synthesized via a surface activation method, and its high porous (~11 nm) surface enhanced the loading content of the desired drug. SCHSs are an infrared photothermal material that can destroy targeted cells by heated under NIR laser illumination at 808 nm. The aim of this thesis is to study the chemo-photothermal effects on liver cancer cells. Two parts of studies are included: (1) To identify the photothermal effect of silica-carbon hollow sphere–concanavalin A on liver cancer cells; (2) To apply the SCHSs as drug delivery system based on its hollow sphere structure. We will further investigate the anti-tumor efficacy of drug-loaded ConA-SCHSs for chemo-photothermal cancer therapy. The first part of this thesis showed that ConA was used to conjugate with silica-carbon hollow spheres (SCHSs) which can be applied in the thermal ablation therapy for liver cancer cell lines under near-infrared (NIR) laser irradiation. The cytotoxic effect of ConA-SCHSs was confirmed by Hoechst 33342 staining assay that the ConA-SCHSs did not exert a cytotoxic effect on all of the hepatocyte (NeHepLxHT) and hepatoma (ML-1 and Huh-7) cell lines, even though the treatment was carried out with high concentrations (500:200 g/mL) of ConA-SCHSs for 24 hours. This result indicated good biocompatibility of SCHSs. Moreover, we found that the amount of ConA-SCHS complex binding to hepatoma cells was significantly higher than as seen on normal hepatocytes (about two to six fold) using flow cytometric analysis and confocal imaging. Most ConA-FITC-SCHSs were located close to the plasma membrane, and others were localized in the cytoplasm. Hepatoma cells incubated with ConA-SCHSs were thus more easily killed by the subsequent irradiation with a NIR laser (0.72 W/cm2). The results showed that the ConA-SCHS complex may enhance the interaction with highly expressed ConA receptors on hepatoma cells, and thus serve as an effective photothermal therapy (PTT) agent for liver cancer treatment. The second part of this thesis was to examine chemo-photothermal effects of doxorubicin/silica-carbon hollow spheres on liver cancer. DOX was loaded on SCHSs by using heat and vacuum to achieve a high encapsulation rate (~90%). Additionally, NIR laser illumination is supposed to enhance DOX release from SCHSs and increase cell membrane permeability, leading to increase the anti-cancer efficiency of DOX. We found that SCHSs exhibited high heat-generating ability (~55°C) and pH-responsive drug delivery. The DOX release rate increased (~35%) when the pH value change from 7.4 to 5.5. Live-Dead cell assay were used to calculate relative cell viability, proving that the percentage of cell death can reach up to 65% with SCHSs under 808-nm NIR illumination (9 W/cm2, 3 minutes), while using DOX/SCHSs induced by NIR illumination can reach a higher cell death rate (approximately 95%). In conclusion, this study has demonstrated that DOX-loaded SCHSs represent a potential tool for chemo-photothermal therapy due to its photothermal effects.
論文目次 中文摘要.................................................I
Abstract..............................................III
誌 謝................................................V
Figure contents........................................IX
Abbreviation list......................................XI
Chapter 1 Introduction..................................1
Chapter 2 Materials and methods.........................7
2.1 Chemicals...........................................7
2.2 Synthesis of the silica-carbon hollow spheres.......7
2.3 Characterization of SCHSs...........................7
2.4 Infrared photothermal behavior of the SCHSs in solution................................................8
2.5 Preparation of ConA(-FITC)-SCHSs....................8
2.6 Preparation of DOX-SCHSs............................8
2.7 Drug release of DOX-SCHSs...........................9
2.8 Cell culture........................................9
2.9 Confocal imaging...................................10
2.10 Cell viability....................................10
2.11 Flow cytometry....................................11
2.12 Photothermal therapy..............................11
2.13 Chemo-photothermal therapy........................11
2.14 Statistical analysis..............................12
Chapter 3 The photothermal effect of silica-carbon hollow
sphere-concanavalin A on liver cancer cells............13
Results................................................14
3.1 Morphology of silica-carbon hollow spheres.........14
3.2 Thermal analysis of silica-carbon hollow spheres...14
3.3 The binding capacity of ConA-FITC-SCHSs and liver cancer cells...........................................15
3.4 Cytotoxicity of ConA-SCHSs on normal and cancerous liver cells............................................16
3.5 The binding capacity of hepatocyte and hepatoma cells with ConA-SCHSs........................................16
3.6 ConA-FITC-SCHSs-mediated photothermal effect.......17
Discussion.............................................19
Chapter 4 Chemo-photothermal effects of doxorubicin/silica-carbon hollow spheres on liver cancer .......................................................22
Results................................................23
4.1 Morphology of silica-carbon hollow spheres.........23
4.2 Characterization of DOX-silica-carbon hollow spheres .......................................................23
4.3 DOX encapsulation and release in vitro.............24
4.4 In vitro cytotoxicity effects on hepatoma cells....26
4.5 In vitro cancer cell killing by DOX-SCHSs..........27
Discussion.............................................29
Chapter 5 Conclusion...................................31
Chapter 6 Future Works.................................33
Acknowledgments........................................35
References.............................................36
Figures................................................41
Curriculum vitae.......................................72
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