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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林文貞(Wen-Jen Lin) | |
dc.contributor.author | Chia-Wen Liu | en |
dc.contributor.author | 劉佳雯 | zh_TW |
dc.date.accessioned | 2021-06-07T17:55:53Z | - |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-15 | |
dc.identifier.citation | Acharya S, Dilnawaz F, Sahoo SK (2009) Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials 30(29): 5737-5750
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15937 | - |
dc.description.abstract | 上皮生長因子受體(Epidermal growth factor receptor)廣泛表現在上皮腫瘤細胞表面,在癌症標靶治療研究中,上皮生長因子受體受到長期的重視。本研究發現並證實一具主動標的至上皮生長因子受體能力之NR7胜肽配體,NR7胜肽配體具主動標的至乳癌細胞MDA-MB-468及卵巢癌細胞SKOV3之細胞表面表現上皮生長因子受體之特異性,MDA-MB-468細胞和SKOV3細胞吞噬NR7胜肽配體能力具有時間相依性及濃度相依性。
本研究選擇聚乳酸-甘醇酸-聚乙二醇高分子(Poly(D,L-lactide-co-glycolide)-poly(ethylene glycol))作為具生物相容性及生物可分解性之奈米粒子材料,因此進行聚乳酸-甘醇酸-聚乙二醇高分子合成並製備為奈米粒子,探討合成高分子與奈米粒子之物化性質,聚乙二醇接枝率為90.9 mol%,臨界微膠粒濃度為3.0 × 10-8 mole/L,聚乳酸-甘醇酸-聚乙二醇奈米粒子粒徑小於200 nm,且粒徑分布均一,聚乳酸-甘醇酸奈米粒子和聚乳酸-甘醇酸-聚乙二醇奈米粒子之50%有效抑制細胞生長濃度分別為1.09 mg/mL和大於100 mg/mL,結果顯示聚乙二醇接枝可降低奈米粒子細胞毒性98倍以上。 本研究進行兩種將具上皮生長因子受體主動標能力之NR7胜肽配體接枝至合成聚乳酸-甘醇酸-聚乙二醇奈米粒子的方法,第一種方式為先將NR7胜肽配體接枝至合成聚乳酸-甘醇酸-聚乙二醇高分子,再進行奈米粒子製備;第二種方式是先進行聚乳酸-甘醇酸-聚乙二醇奈米粒子製備,再進行NR7胜肽配體接枝步驟。高度表現上皮生長因子受體之MDA-MB-468細胞和SKOV3細胞均高度吞噬以這兩種接枝方式得到之NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子,但低表現上皮生長因子受體之HepG2肝癌細胞吞噬能力較低;MDA-MB-468細胞和SKOV3細胞吞噬NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子能力高於未接NR7胜肽配體奈米粒子。NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子進入細胞後,主要位於細胞質和細胞核,MDA-MB-468細胞和SKOV3細胞吞噬機制研究顯示,NR7胜肽配體-奈米粒子是利用NR7胜肽配體主動標的於上皮生長因子受體並經由上皮生長因子受體轉介之細胞內吞作用(EGFR-mediated endocytosis)進入細胞,進入核內體-溶小體路徑(endolysosomal pathway)。 NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子進一步應用於包覆小分子藥物-艾黴素(doxorubicin)和大分子藥物-小干擾RNA(siRNA),分別為艾黴素-NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子及小干擾RNA-NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子,這兩種藥物奈米粒子粒徑約在200 nm,粒徑分布均一。在模擬溶小體的環境中,艾黴素及小干擾RNA的釋放速率比在pH 7.4緩衝溶液中快速,這表示聚乳酸-甘醇酸-聚乙二醇高分子會在酸性環境中會被水解,亦會被脂肪分解酵素降解,因此在全身血液循環之中性環境下,艾黴素及小干擾RNA會被穩定地包覆在奈米粒子中,當NR7胜肽配體-奈米粒子是利用NR7胜肽配體主動標的於上皮生長因子受體進入溶小體時,艾黴素及小干擾RNA會從奈米粒子被釋放出來。在細胞生長抑制實驗中,艾黴素-NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子對SKOV3和MDA-MB-468之50%有效抑制細胞生長濃度分別比艾黴素-聚乳酸-甘醇酸-聚乙二醇奈米粒子低62.4倍和2.21倍,此結果顯示NR7胜肽配體可指引奈米粒子主動標的至高度表現上皮生長因子受體癌症細胞,並增加奈米粒子遞送藥物毒殺癌症細胞之療效。 在細胞實驗中,以NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子同時遞送艾黴素及小干擾RNA比單獨遞送艾黴素或小干擾RNA造成較高的細胞毒殺效果。在SKOV3腫瘤生長抑制動物實驗中,接受NR7胜肽配體奈米粒子同時遞送艾黴素及小干擾RNA治療的小鼠,其腫瘤體積為僅接受艾黴素及小干擾RNA治療小鼠腫瘤的52.6%,另為接受奈米粒子同時遞送艾黴素及小干擾RNA的50.2%;在細胞實驗及動物實驗結果顯示,小干擾RNA在此藥物遞送系統中扮演艾黴素之化藥增敏作用(chemosensitization)的角色。 在小鼠SKOV3腫瘤之藥物生體組織分佈試驗中,以NR7胜肽配體奈米粒子及不具NR7胜肽配體奈米粒子均比艾黴素溶液遞送較高量的艾黴素在腫瘤中 (p < 0.05),此為奈米粒子之促進性滲透與滯留效應(enhanced permeation and retention effect),亦稱為被動標的(passive targeting);此外,NR7胜肽配體奈米粒子會利用SKOV3細胞表面高度表現上皮生長因子受體之細胞內吞作用,送入更多艾黴素進入細胞,稱為主動標的(active targeting)。結合主動標的及被動標的效果,在小鼠藥物生體組織分佈試驗中,具NR7胜肽配體奈米粒子較奈米粒子遞送高2.6倍艾黴素至腫瘤處。 因此本研究發展出一具有上皮生長因子受體主動標的能力之NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子,此NR7胜肽配體奈米粒子不只增加遞送至細胞質內藥物累積量,亦可遞送藥物至細胞核附近或細胞核內,本NR7胜肽配體奈米粒子已應用在小分子藥物(艾黴素)及大分子基因(小干擾RNA)遞送至高度表現上皮生長因子受體之癌症細胞治療,此奈米載體亦為酸鹼及酵素釋放控制之抗癌藥物傳輸系統,可控制藥物在進入高度表現上皮生長因子受體細胞後才從奈米粒子內釋放,因此,NR7胜肽配體-聚乳酸-甘醇酸-聚乙二醇奈米粒子提供一具有上皮生長因子受體主動標的能力、具有生物相容性之藥物遞送載體應用。 | zh_TW |
dc.description.provenance | Made available in DSpace on 2021-06-07T17:55:53Z (GMT). No. of bitstreams: 1 ntu-101-D96423003-1.pdf: 3357906 bytes, checksum: acbd5dd276f641b01f14b54301a77037 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 論文口試委員審定書 I
致謝 III Abstract (Chinese) V Abstract (English) IX 1. Introduction 1 1.1. Poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) nanoparticles 1 1.2. Epidermal growth factor receptor 2 1.3. NR7 peptide 3 1.4. Doxorubicin 4 1.5. Vascular endothelial growth factor siRNA 5 2. Purpose 6 3. Materials and Equipments 7 3.1. Materials 7 3.2. Equipments 9 4. Experimental Methods 11 4.1. Abbreviation 11 4.2. Flow chart of nanoparticles preparation 12 4.3. Synthesis of Tosyl PEG 13 4.4. Synthesis of Phthalimide PEG 14 4.5. Synthesis of Aminopoly(ethylene glycol) (Amino-PEG) 15 4.6. Preactivation of PLGA 15 4.7. Synthesis of PLGA-PEG amphiphilic copolymer 16 4.8. Synthesis of PLGA-PEG-FITC and PLGA-PEG-Peptide-FITC copolymers 17 4.9. Determination of polymer molecular weight 19 4.10. Determination of critical micelle concentration (CMC) 19 4.11. Determination of particle size and zeta potential 20 4.12. Cytotoxicity study 20 4.13. Cellular uptake NR7 peptide study 21 4.14. SKOV3 cellular uptake of PLGA-PEG-FITC and PLGA-PEG-Peptide-FITC nanoparticles 22 4.15. Synthesis of PLGA-PEG-FITC copolymer and PLGA-PEG-Peptide-FITC copolymer using commercial PEG diamine 22 4.16. Preparation of PLGA-PEG-FITC and PLGA-PEG-Peptide-FITC nanoparticles 23 4.17. Synthesis and preparation of PLGA-PEG nanoparticles-FITC and PLGA-PEG nanoparticles-Peptide-FITC 24 4.18. Cellular uptake of nanoparticles study 25 4.19. Mechanism study 26 4.20. Intracellular tracking of nanoparticles study 27 4.21. NR7-peptide conjugated with Cy5.5-NHS study 27 4.22. PLGA-PEG nanoparticles-Cy5.5 and PLGA-PEG nanoparticles-Peptide-Cy5.5 28 4.22.1. Conjugation and characterization 28 4.22.2. Cellular uptake study 30 4.22.3. In vivo biodistribution study 30 4.23. Doxorubicin-loaded PLGA-PEG and PLGA-PEG-Peptide nanoparticles 31 4.23.1. Preparation and characterization 31 4.23.2. In vitro release study 33 4.23.3. Cytotoxicity study 33 4.24. siRNA/DOTAP-loaded PLGA-PEG-Peptide nanoparticles 34 4.24.1. Preparation and characterization 34 4.24.2. In vitro release study 36 4.24.3. Cytotoxicity study 36 4.25. Cytotoxicity study of doxorubicin-loaded PLGA-PEG-Peptide nanoparticle and siRNA/DOTAP-loaded PLGA-PEG-Peptide nanoparticle co-treatment 37 4.26. Biodistribution study of doxorubicin-loaded PLGA-PEG-Peptide nanoparticle in vivo 37 4.27. Tumor growth inhibition study in vivo 39 5. Results and discussion 40 5.1. Characterization of Aminopoly(ethylene glycol) (Amino-PEG) 40 5.2. Characterization of PLGA-PEG 44 5.3. Critical micelle concentration (CMC) of PLGA-PEG 48 5.4. Particle size and TEM image of PLGA-PEG nanoparticles 49 5.5. Cellular viability of PLGA-PEG nanoparticles 52 5.6. Cellular uptake NR7-FITC peptide study 55 5.7. Characterization of PLGA-PEG-FITC and PLGA-PEG-Peptide-FITC nanoparticles 62 5.8. SKOV3 cellular uptake of PLGA-PEG-FITC and PLGA-PEG-Peptide-FITC nanoparticles 64 5.9. Synthesis and characterization of PLGA-PEG-FITC copolymer and PLGA-PEG-Peptide-FITC copolymer 67 5.10. Synthesis and characterization of PLGA-PEG nanoaprticles Peptide-FITC copolymer 71 5.11. Characterization of PLGA-PEG-FITC nanoparticles, PLGA-PEG-Peptide-FITC nanoparticles, PLGA-PEG nanoparticles-FITC and PLGA-PEG nanoparticles-Peptide-FITC 74 5.12. Cellular uptake of the PLGA-PEG-FITC nanoparticles and PLGA-PEG-Peptide-FITC nanoparticles 80 5.13. Cellular uptake of the PLGA-PEG nanoparticles-FITC and PLGA-PEG nanoparticles-Peptide-FITC 83 5.14. Mechanism study of PLGA-PEG-FITC nanoparticles and PLGA-PEG-Peptide-FITC nanoparticles 87 5.15. Competitive study of PLGA-PEG-FITC nanoparticles and PLGA-PEG-Peptide-FITC nanoparticles 91 5.16. Intracellular tracking of PLGA-PEG-Peptide-FITC nanoparticles and PLGA-PEG nanoparticles-Peptide-FITC 98 5.17. Proposed model 101 5.18. NR7-peptide conjugated with Cy5.5-NHS study 104 5.19. PLGA-PEG nanoparticles-Cy5.5 and PLGA-PEG nanoparticles-Peptide-Cy5.5 107 5.19.1. characterization 107 5.19.2. Cellular uptake of the PLGA-PEG nanoparticles-Cy5.5 and PLGA-PEG nanoparticles-Peptide-Cy5.5 109 5.19.3. Accumulation of PLGA-PEG nanoparticles-Cy5.5 and PLGA-PEG nanoparticles-Peptide-Cy5.5 in SKOV3 tumor-bearing mice 110 5.20. Doxorubicin-loaded PLGA-PEG-Peptide nanoparticles 112 5.20.1. Characterization 112 5.20.2. In vitro release study 114 5.20.3. Cytotoxicity study 117 5.21. In vivo biodistribution study of doxorubicin-loaded PLGA-PEG-Peptide nanoparticles 129 5.22. siRNA/DOTAP-loaded PLGA-PEG-Peptide nanoparticles 138 5.22.1. Characterization 138 5.22.2. In vitro release study 143 5.22.3. Cytotoxicity study 146 5.23. Cytotoxicity study of doxorubicin-loaded PLGA-PEG-Peptide nanoparticle and siRNA/DOTAP-loaded PLGA-PEG-Peptide nanoparticle co-treatment 150 5.24. Pharmacodynamic study in vivo 154 6. Conclusion 159 7. Prospective 163 8. References 164 | |
dc.language.iso | en | |
dc.title | 胜肽配體結合奈米粒主動標的於上皮生長因子受體之研究 | zh_TW |
dc.title | Study on peptide ligand conjugated nanoparticles active targeting to epidermal growth factor receptor | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 江樵熹,陳錦龍,孔繁璐,沈麗娟 | |
dc.subject.keyword | 上皮生長因子受體,聚乳酸-甘醇酸,奈米粒子,胜肽,配體,艾黴素,小干擾RNA, | zh_TW |
dc.subject.keyword | epidermal growth factor receptor,poly(D,L-lactic-co-glycolic acid),nanoparticles,peptide,doxorubicin,siRNA, | en |
dc.relation.page | 183 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2012-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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