pH感應性中孔洞奈米矽球於抗藥性癌症之應用

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研究生：	黃怡萍 Huang, I-Ping
論文名稱：	pH感應性中孔洞奈米矽球於抗藥性癌症之應用 Enhanced Chemotherapy of Cancer Using pH-Responsive Mesoporous Silica nanoparticles Orchestrating Targeted Delivery, Drug Resistance Mediation and Apoptotic Activation
指導教授：	黎耀基 Lai, Yiu-Kay 羅履維 Lo, Leu-Wei
口試委員:	楊重熙李文權吳立真
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	160
中文關鍵詞：	中孔洞奈米矽球、pH感應性、多重抗藥性、P-醣蛋白
外文關鍵詞：	mesoporous silica nanoparticles, pH-responsive, multidrug resistance, P-glycoprotein
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近十年來，利用奈米粒子作為載體來傳遞抗癌藥物到癌細胞的技術已逐漸蓬勃發展。奈米粒子依其化學結構可廣泛分類為有機、無機和複合型奈米粒子。本篇研究主要在建立一個利用無機材料中孔洞奈米矽球來進行藥物控制釋放的活體奈米系統。此中孔洞奈米矽球具有高表面積、可調控的孔洞大小、高熱穩定性、生物相容性及三個可個別修飾的區域（骨架、孔洞及外表面）。本篇主要探討以下三個主題：(1) pH感應性中孔洞奈米矽球於細胞內抗癌藥物之控制釋放，(2)利用pH感應性中孔洞奈米矽球對抗P-glycoprotein所引起的多重抗藥性，以增加癌症化療效果，及(3) pH感應性中孔洞奈米矽球結合Doxorubicin與TNFα在多重抗藥性腫瘤中具有協同性抑制作用。
主題(1)：pH感應性中孔洞奈米矽球之藥物傳遞系統具有一些引人注目的特色，包括(i)持續性的藥物釋放，(ii)減少因酵素水解造成的藥物釋放，(iii)經由簡單的表面電性修飾即可增加細胞吞噬效果，(iv)增加藥物裝載量及釋放效果。在細胞內的內胞體及溶小體等酸性環境下，藉由水解pH感應性鍵結(hydrazone bond)造成doxorubicin從中孔洞奈米矽球的孔洞中釋放出來，進而造成顯著的細胞凋亡。
主題(2)：多重抗藥性癌細胞是目前臨床癌症化療的一項重大障礙，而造成癌細胞多重抗藥性最重要的因子是癌細胞高度表達將藥物排出癌細胞外的跨膜幫浦P-glycoprotein (PGP)，導致有效藥物在細胞內的濃度不足。因此我們利用pH感應性中孔洞奈米矽球來克服PGP所引起的多重抗藥性問題， pH感應性中孔洞奈米矽球是藉由胞吞作用進入細胞，在內胞體及溶小體等酸性環境下持續性釋放藥物，實驗證明藥物幾乎不會被PGP排出細胞外。在體外及活體實驗結果均顯示以pH感應性中孔洞奈米矽球進行Doxorubicin的控制釋放，在人類子宮惡性肉瘤抗藥性細胞中造成顯著的細胞凋亡。
主題(3)：文獻指出腫瘤壞死因子(TNFα)同時具有標靶藥物傳遞及抗腫瘤的特性，因此我們將TNFα修飾在pH感應性中孔洞奈米矽球的表面，而孔洞中裝載抗癌藥物Doxorubicin，希望有協同性抑制腫瘤的效果。初步結果顯示，此協同作用機制可能是由Doxorubicin及TNFα連續性引發細胞凋亡所造成的結果，而活體實驗應用有待後續研究繼續努力。
總結，本研究利用中孔洞奈米矽球結合臨床抗癌藥物應用於標靶藥物傳遞及藥物控制釋放，由結果證明具有協同性抑制腫瘤的效果，未來，此奈米系統在生物醫學上之應用極具潛力性。

Chinese abstract     i
English abstract     iii
List of Tables     x
List of Figures     xi
Abbreviations     xv
Chapter 1 : General Introduction     1
1-1 Nanoparticles and drug delivery     2
1-2 Targeted drug delivery     3
1-3 Nanoparticles for controlled release of anticancer drug     4
1-4 pH-sensitive drug delivery system (DDS)     5
1-5 MSNs for drug delivery     7
1-5-1 Controlled release and targeted drug delivery of MSNs     7
1-5-2 Pharmacokinetics of MSNs     8
1-5-2-1 Biodegradation     8
1-5-2-2 Biodistribution, retention and excretion     9
1-6 Propose of This Study     10
1-7 Table and Figures     12
Chapter 2 : Intracellular pH-Responsive Mesoporous Silica Nanoparticles for Controlled Release of Anticancer Chemotherapeutics     29
2-1 Abstract     30
2-2 Introduction     30
2-3 Materials and Methods     33
2-3-1 Experimental reagents     33
2-3-2 Cell Line and Animal     33
2-3-3 Preparation of Atto647-MSN     34
2-3-4 Synthesis of trimethylammonium (TA)-modified MSN     34
2-3-5 Synthesis of Aldehyde-modified (Atto647)-MSN     35
2-3-6 Conjugation of adipic acid dihydrazide in aldehyde-modified MSN (MSN-hydrazide)     35
2-3-7 Doxorubicin conjugated with MSN-hydrazide (MSN-hydrazone-Dox)     36
2-3-8 In vitro release studies     36
2-3-9 Confocal microscopy     36
2-3-10 TUNEL assay     37
2-3-11 Cell Viability via DNA fragmentation     37
2-3-12 Cell Viability via MTT Assay     38
2-3-13 TEM Imaging and Compositional Element Analysis of Cell Ultra-sections     39
2-3-14 TEM Imaging of Liver Tissue-sections     39
2-3-15 In vivo Optical Imaging     40
2-3-16 Characterization     40
2-4 Results and Discussions     41
2-4-1 Synthesis and modification of various doxorubicin conjugated MSN-hydrazide     41
2-4-2 Schematic illustration of pH-sensitive MSN drug delivery platform     42
2-4-3 Characterization of morphology, surface area and pore size of MSNs     42
2-4-4 Characterization of chemical bonds and surface organic groups of   MSNs     43
2-4-5 pH-sensitive release doxorubicin of MSN-Hydrazone-Dox     44
2-4-6 Cellular uptake of Atto647-labeled MSN-Hydrazone-Dox     46
2-4-7 MSN-Hydrazone-Dox induce cell apoptosis detect by TUNEL assay     47
2-4-8 MSN-Hydrazone-Dox enhances cytotoxicity of HepG2 cells     48
2-4-9 Biodistribution of Atto647-MSN-Hydrazone-Dox in mice     49
2-5 Conclusions     50
2-6 Table     51
2-7 Figures     52
Chapter 3 : Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein-Mediated Drug Resistance     64
3-1 Abstract     65
3-2 Introduction     65
3-3 Materials and Methods     69
3-3-1 Experimental reagents     69
3-3-2 Cell Line     69
3-3-3 Cellular Retention of Doxorubicin     70
3-3-4 Confocal Microscopy     70
3-3-5 In vitro Cytotoxicity     71
3-3-6 DNA Fragmentation     71
3-3-7 The TUNEL assay     72
3-3-8 Animal model     72
3-3-9 TEM Imaging of tumor tissue     73
3-3-10 Immunohistochemistry     73
3-3-11 P-glycoprotein detection by Flow Cytometry     74
3-3-12 Membrane protein extraction and Western blot     74
3-4 Results     75
3-4-1 MSN-Hydrazone-Dox enhances cellular retention of doxorubicin     75
3-4-2 MSN-Hydrazone-Dox is uptaken by the MES-SA/Dx5 cancer cell  through endocytosis     76
3-4-3 MSN-Hydrazone-Dox enhances cytotoxicity of the MES-SA/Dx5   cancer cells    76
3-4-4 MSN-Hydrazone-Dox but not MSN-Hydrazone induces and enhances apoptosis in MES-SA/Dx5 cells     77
3-4-5 MSN-Hydrazone-Dox is uptaken and induces apoptosis of tumor cells   in vivo    78
3-5 Discussion     78
3-6 Conclusions     81
3-7 Figures     82
Chapter 4 : Enhanced Anticancer Effect of the Combination of Doxorubicin- and TNFα-conjugated pH-Responsive Mesoporous Silica Nanoparticles in Multidrug Resistant Tumor     92
4-1 Introduction     93
4-2 Materials and Methods     95
4-2-1 Experimental reagents     95
4-2-2 Cell Line     96
4-2-3 Preparation of Atto647-MSN     96
4-2-4 Synthesis of Aldehyde-modified (Atto647)-MSN     97
4-2-5 Conjugation of adipic acid dihydrazide in aldehyde-modified MSN (MSN-hydrazide)     97
4-2-6 Doxorubicin conjugated with MSN-hydrazide (MSN-hydrazone-Dox)     98
4-2-7 Surface Modification of MSN-hydrazone-Dox with PEG     98
4-2-8 Surface Modification of PEGylated MSN-hydrazone-Dox with TA     98
4-2-9 TNFα conjugation of PEGylated MSN-hydrazone-Dox     99
4-2-10 In vitro release studies     99
4-2-11 ELISA assay     99
4-2-12 Confocal microscopy     100
4-2-13 Cell Viability via MTT Assay     100
4-2-14 TNFR1 detection by Flow Cytometry     101
4-2-15 Characterization     101
4-3 Results and Discussions     102
4-3-1 Synthesis of TNFα-PEG-MSN-hydrazone-Dox     102
4-3-2 Schematic illustration of TNFα-conjugated pH-sensitive MSN drug delivery system     103
4-3-3 Characterization of morphology and size of MSNs     104
4-3-4 pH-sensitive release doxorubicin of PEG-MSN-Hydrazone-Dox     104
4-3-5 Cellular uptake of Atto647-labeled TNFα-PEG-MSN-hydrazone-Dox      105
4-3-6 TNFα-PEG-MSN-Hydrazone-Dox enhances cytotoxicity of  MES-SA/Dx5 cells     106
4-4 Summary     106
4-5 Table     107
4-6 Figures     108
References     115
Publication list     130
Appendix     131

                                

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