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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林?輝 | |
| dc.contributor.author | Wei-Ting Kuo | en |
| dc.contributor.author | 郭韋廷 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:45:00Z | - |
| dc.date.copyright | 2015-09-02 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-05 | |
| dc.identifier.citation | [1] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
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Bioessays 2006;28:253-260. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17865 | - |
| dc.description.abstract | 發展針對表皮生長因子接受器的標靶分子，可以有效改善傳統非小細胞癌治療的缺陷，例如缺乏標定的選擇性與對正常細胞造成的毒性。植物凝集素E是一種來自大紅豆的萃取物，它可以封鎖表皮生長因子接受器的活化，進而誘導肺癌細胞凋亡。明膠常被用來當作藥物傳輸系統的載體，因為具有生物相容性、生物可降解性、低細胞毒性、並且有很多活化的官能基，可以用來接枝標靶分子像是植物凝集素E，並且可以攜帶化療藥物例如健擇。 由於表皮生長因子是植物凝集素E於臨床運用上在人體內最主要的競爭者，所以植物凝集素E首先必須先證明其與表皮生長因子接受器間的結合力優於表皮生長因子與其接受器間的結合力。首先，我們用原子力顯微鏡來測量附著力，由實驗結果可以發現，植物凝集素E與表皮生長因子接受器間有較高的附著力。我們也用表面電漿共振儀來量測親合力，植物凝集素E與表皮生長因子接受器間有一樣有較高的親合力。而從流式細胞儀和共軛焦顯微鏡的結果來看，當植物凝集素E在培養液中的濃度提高時，表皮生長因子結合率會下降。另外，從西方點墨法的試驗當中發現，當植物凝集素E濃度提高時，一樣也會減少表皮生長因子與接受器結合，導致表皮生長因子接受器無法被磷酸化進而抑制癌細胞生長。 本實驗以奈米沉澱法來合成明膠奈米粒子，並結合植物凝集素E與化療藥物健擇，使奈米粒子所攜帶的藥物透過植物凝集素E標定到肺癌細胞。本實驗所合成的明膠奈米粒子為均一奈米大小的圓形顆粒，粒徑為290奈米。而從明膠奈米粒子所釋放出來的健擇其釋放曲線在72小時達到平穩，累積的釋放量只有30%。此外，有結合植物凝集素E的明膠奈米粒子確實較容易標定到肺癌細胞A-549與H292。結合植物凝集素E與攜帶健擇之明膠奈米粒子可以有效抑制肺癌細胞的生長且造成其細胞毒性。由annexin V/PI雙染法結果證實，結合植物凝集素E與攜帶健擇之明膠奈米粒子會誘導肺癌細胞凋亡。最後，從西方點墨法的結果顯示，結合植物凝集素E與攜帶健擇之明膠奈米粒子會抑制表皮生長因子接受器與Akt的磷酸化表現，進而導致Bad的磷酸化表現也被抑制，同時也會活化p53的磷酸化表現，進而活化Bax，以上結果共同促使cytochrom c的釋放，進而活化最下游的caspase-9與caspase-3，因而誘導肺癌細胞凋亡。 總結上述結果，我們發現植物凝集素E與表皮生長因子接受器間有較高的結合力，因此可以有效競爭且降低表皮生長因子與其接受器的結合，進而可與奈米藥物載體結合，標定至肺癌細胞。本實驗所合成的結合植物凝集素E與攜帶健擇之明膠奈米粒子可抑制表皮生長因子接受器並且啟動p53，進而誘導肺癌細胞凋亡，導致其產生細胞毒性並抑制生長。結合植物凝集素E與攜帶健擇之明膠奈米粒子具有發展成為抗肺癌藥物之潛力。 | zh_TW |
| dc.description.abstract | The development of epidermal growth factor receptor (EGFR)-targeting biomolecules would have a chance to improve the lack of target selectivity and toxicity profile of traditional treatments for non-small cell lung cancer (NSCLC). Phytohemagglutinin erythroagglutinating (PHA-E) is a natural product extracted from red kidney beans, and it has been reported to induce cell apoptosis by blocking EGFR in NSCLC. Gelatin is one of efficient drug delivery vehicles due to its biocompatibility, biodegradability, low cytotoxicity, and numerous available active groups for attaching targeting molecules like PHA-E and carried NSCLC chemotherapeutic agent gemcitabine. Because epidermal growth factor (EGF) is the major in vivo competitor to PHA-E in clinical application, PHA-E must be proved that has better binding ability to EGFR than that of EGF. The adhesion force, measured by AFM, between EGFR and PHA-E was 207.14±74.42 pN that was higher than EGF (183.65±86.93 pN). The equilibrium dissociation constant of PHA-E and EGF to EGFR was 2.4×10-9 | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:45:00Z (GMT). No. of bitstreams: 1 ntu-104-D00548012-1.pdf: 6378159 bytes, checksum: 55e6a278841e7b67a6bfa4c8f860330e (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書 # 誌謝 i 中文摘要 ii ABSTRACT iv CONTENTS vi LIST OF FIGURES viii LIST OF TABLES ix LIST OF ABBREVIATION x Chapter 1 Introduction 1 1.1 Lung cancer 1 1.1.1 The histologic classification of lung cancer 1 1.1.2 Lung cancer staging 3 1.1.3 Lung cancer treatment 4 1.1.3.1 Chemotherapy 4 1.1.3.1.1 Gemcitabine 5 1.1.3.2 Targeted therapy 5 1.2 Epidermal growth factor receptor 10 1.2.1 EGFR inhibitors 10 1.3 Phytohemagglutinin erythroagglutinating 15 1.4 Nanoparticles for drug delivery in cancer therapy 17 1.4.1 Gelatin nanoparticles for drug delivery 18 1.5 Object of study 24 Chapter 2 Theoretical basis 25 2.1 Biomolecular interaction analysis 25 2.1.1 Atomic force microscopy 25 2.1.2 Surface plasmon resonance 26 2.2 Apoptosis 31 2.2.1 Gemcitabine-induced apoptosis 33 2.2.2 PHA-E-induced apoptosis 34 2.3 Characterization of gelatin 40 2.3.1 Nanoprecipitation method for gelatin nanoparticle preparation 40 2.3.2 Drug release of gelatin nanoparticles 41 2.4 Receptor-mediated endocytosis of nanoparticles 44 2.5 Aerosol delivery of nanoparticles 47 Chapter 3 Materials and Methods 49 3.1 Flow chart 49 3.2 Material 51 3.2.1 Chemicals and reagents 51 3.2.2 Consumables 53 3.2.3 Instruments 53 3.3 Binding ability of PHA-E to EGFR compared with EGF 55 3.3.1 Modification of AFM tips and sensor CM5 chips 55 3.3.2 Adhesion force measurements 55 3.3.3 Binding affinity analysis 56 3.3.4 Cell culture 56 3.3.5 EGF binding assay 56 3.3.6 Immunofluorescent staining 57 3.3.7 Western blot analysis 57 3.3.8 Statistical analysis 58 3.4 Preparation of gelatin nanoparticles conjugated PHA-E and carried gemcitabine 59 3.4.1 Preparation of fluorescent gelatin nanoparticles (GNP) 59 3.4.2 PHA-E and gemcitabine conjugated on the surface of GNP 59 3.5 Material characteristics 63 3.5.1 Morphology of GNP 63 3.5.2 Particle size 63 3.5.3 Drug loading and release 63 3.6 In vitro study 65 3.6.1 Cell culture 65 3.6.2 Cellular uptake of nanoparticles 65 3.6.3 WST-1 assay 66 3.6.4 LDH assay 66 3.6.5 LIVE/DEAD assay 67 3.6.6 Annexin V/PI Assay 67 3.6.7 Western blot analysis 68 3.6.8 Statistical analysis 68 Chapter 4 Results 69 4.1 The measurement of adhesion force by AFM 69 4.2 The evaluation of binding affinity by SPR 72 4.3 The competition of PHA-E and EGF bind to EGFR 74 4.4 The effect of competition between PHA-E and EGF on EGFR phosphorylation 78 4.5 Characterization of nanoparticles 80 4.6 The gemcitabine loading and release profile 82 4.7 Cellular accumulation of nanoparticles 84 4.8 Cell viability and cytotoxicity 87 4.9 Live and dead cells staining 89 4.10 Nanoparticles-induced apoptosis 91 4.11 Nanoparticles-induced apoptotic pathway 93 Chapter 5 Discussion 95 Chapter 6 Conclusion 101 REFERENCES 102 | |
| dc.language.iso | en | |
| dc.title | 發展結合植物凝集素E與攜帶健擇之明膠奈米粒子於非小細胞肺癌治療之運用 | zh_TW |
| dc.title | Development of gelatin nanoparticles conjugated with phytohemagglutinin erythroagglutinating and carried gemcitabine for non-small cell lung cancer treatment | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 姚俊旭,郭士民,張淑真,陳中明,謝文元 | |
| dc.subject.keyword | 表皮生長因子接受器,明膠奈米粒子,肺癌,奈米沉澱法,植物凝集素E, | zh_TW |
| dc.subject.keyword | epidermal growth factor receptor,gelatin nanoparticle,lung cancer,nanoprecipitation,phytohemagglutinin erythroagglutinating, | en |
| dc.relation.page | 111 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-08-05 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
| 顯示於系所單位： | 醫學工程學研究所 | |
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