以醣胺多醣結合胜肽應用於胞內輸送及腫瘤標靶

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研究生：	陳建榮 Chen, Chien Jung
論文名稱：	以醣胺多醣結合胜肽應用於胞內輸送及腫瘤標靶 A Multifunctional Glycosaminoglycan Binding Peptide for Intracellular Delivery and Tumor Targeting—From Basic Research to Translational Application
指導教授：	張大慈 Chang, Dah Tsyr
口試委員:	方韶瓏洪建中蘇士哲周裕珽張顥騰鄭兆勝
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2015
畢業學年度：	104
語文別：	英文
論文頁數：	151
中文關鍵詞：	葡萄胺聚醣標靶胜肽、腫瘤微環境、癌標誌辨識、標靶藥物運輸、癌症抑制
外文關鍵詞：	glycosaminoglycan targeting peptide, tumor microenvironment, cancer biomarker, anti-tumor, targeted drug delivery
相關次數：	點閱：3 下載：0
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惡性腫瘤長期蟬聯全球十大死因首位。近年全球癌症發生率持續增加，死亡率也快速攀升。惡性腫瘤非但生長快速，且經由上皮細胞間質轉化(epithelial-mesenchymal transition、EMT)可侵入其他不同來源的組織或器官內滋生，因此治療性癌標靶藥物及癌標靶藥物運輸的研究與發展是近年備受重視的研究課題。癌變細胞表面分子與其腫瘤微環境間的交互作用相關，目前已知表皮細胞表面負電性蛋白聚醣為細胞外微環境之重要訊號傳遞受器複合體。腫瘤癥兆發生時細胞表面影響生長、分化、細胞外基質重組及癌轉移的蛋白聚醣及其附著之葡萄胺聚醣(Glycosaminoglycan、GAG)會隨之改變表現量與結構，影響腫瘤自分泌及旁分泌配體表現及補充，進而連通及放大腫瘤微環境間訊號傳遞。因此，腫瘤微環境間溝通之阻斷劑為當前研究新方向及醫療迫切需求。本研究率先鑑定一組能辨識細胞表面葡萄胺聚醣並可穿透細胞之短鏈胜肽(Glycosaminoglycan-binding peptide、GBP)，對表皮癌細胞株選擇性高於正常細胞株，且組織微陣列切片染色顯示其對多種肺癌組織具高度辨識能力。利用同種移植之腫瘤小鼠模式研究重組蛋白eGFP-GBP於活體循環組織特異性，免疫化學染色結果顯示eGFP-GBP主要標的為皮下腫瘤處。在同一動物模式中，普魯士染色結果顯示攜帶GBP的磁性奈米粒子(GBP-conjugated magnetic nanoparticle、MNP-GBP)亦具標的至皮下腫瘤的能力。深入探討此新穎葡萄胺聚醣標靶胜肽序列與功能相關性，發現關鍵胺基酸組合特性，更進一步其能抑制腫瘤移行及侵襲。本研究成果已發表於國際期刊並獲證國內外專利，具體貢獻於新型抗癌胜肽設計、化學修飾抗癌藥物合成、及開發以GBP為基礎之表皮癌細胞用藥新型配方與傳輸系統。

Cancers are the leading causes of morbidity and mortality worldwide, among which epithelial lung, liver, stomach, colorectal and breast cancer rank the most common types in sequence. The most lethal aspect of cancer is its increasing capacity to metastasize from primary tumor to liver, lung and other organs through epithelial-to-mesenchymal transition (EMT). Proteoglycans are secreted on the surface of epithelial cells to act as signaling molecules of pericellular microenvironment. As a receptor complex, proteoglycans can switch cell response to certain pathophysiological stimuli. Expression and structure of proteoglycan or glycosaminoglycan (GAG) are significantly altered in cancer progression, leading to recruiting autocrine/paracrine receptor ligands to promote their bioactivities and also induce crosstalk among various families of receptors in tumor microenvironment. A glycosaminoglycan-binding cell penetrating peptide (GBP) can recognize cell surface negatively charged components and transport various cargoes into cells. GBP can probe epithelial cancers with abnormal expression of extracellular GAGs. Screening by multiple cancer tissue arrays has demonstrated that GBP prefers probing all lung tumor types, especially for epithelial cancers. GBP conjugation facilitates cargos eGFP (eGFP-GBP) and magnetic nanoparticle (MNP-GBP) to selectively target tumor site in vivo. Furthermore, GBP with characteristic sequence dependence displays significantly inhibitory effects on migration and invasion of human lung cancer cell. Taken together, our GBP related technology has been published in SCI papers and issued international and domestic patents. GBP could engage its capacity to be diagnostic imaging agent, supplementary therapeutic modality or functionalized vector for drug delivery.

Chapter 1  Introduction    1
Epithelial cancer    1
Proteoglycans and glycosaminoglycans    2
Abnormal expression of proteoglycans and glycosaminoglycans in cancer progression    3
Relationship between HSPG and cell migration/invasion signaling pathway    6
Human RNase A superfamily    7
Glycosaminoglycan binding peptides derived from human RNase A superfamily    11
Cell penetrating peptides for intracellular delivery    11
Mechanism of CPP translocation across cell membrane    13
Drug delivery: CPP-drug conjugates in clinical trials    14
Unmet medical need    16
Market of therapeutic peptides    16
Rationales of study    19
Chapter 2  Materials and Methods    20
2-1  Bacterial strains, vectors, and culture conditions    20
2-2  Cells and cell culture    20
2-3  Competent cell preparation and transformation    21
2-4  Expression of eGFP and eGFP-GBP    22
2-5  Purification of eGFP and eGFP-GBP    22
2-6  Buffer exchange, protein concentration and quantification    23
2-7  Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)    23
2-8  Synthetic Peptides    24
2-9  Enzyme-link immunosorbent assay (ELISA)    24
2-10  Animal model    25
2-11  Immunohistochemistry (IHC) staining    26
2-12  Scoring of Immunohistochemistry Staining    27
2-13  Magnetic nanoparticle conjugated GBP and Prussian blue staining    28
2-14  Hematoxylin & Eosin stain    29
2-15  In vitro cell migration and invasion assay (Transwell® assay)    29
2-16  Statistical analysis    30
Chapter 3  Results    31
Heparan sulfate binding cell penetrating peptides derived from natural proteins    31
In silico analysis of unique peptide regions in hRNaseA superfamily    32
Endocytosis activity of wild type and mutant hRNase3 to Beas-2B cells    33
Binding activity of wild type and mutant hRNase3 to LMWH    33
Binding activity of synthetic peptides FITC-HBPRNase3(32-41), FITC-HBPRNase3(71-80) and HBPRNase3(97-106) to Beas-2B cells    34
Cellular binding activity of hRNase3 and HBPRNase3(32-41)    35
Cytotoxicity of HBPRNase3(32-41) to Beas-2B cells    35
Cellular binding of GBPECP to tumor cell with higher HS expression level    36
Enhancement on GBPECP binding under acidic pH    38
Immunohistochemistry staining in multiple organ cancer    39
Correlation among HS expression, CS expression and eGFP-GBPECP binding to major lung cancers    41
In vivo tissue distribution of eGFP- GBPECP on CT-26 mouse model    43
Tumor targeting of MNP- GBPECP    44
In vivo tissue distribution of eGFP-GBPECP on H1299 mouse model    46
HS expression, CS expression and eGFP-GBPECP targeting on cancer progression    46
Comparison of cellular binding activities among GBPECP and GBP derivatives    47
Comparison of cellular uptake among GBPECP and GBP derivatives    49
Inhibition of cell migration and invasion mediated by GBP and GBP derivatives    50
Expression and purification of recombinant eGFP and eGFP-GBP    52
Chapter 4  Discussion    53
Human RNase3 and heparin binding region of hRNase3    53
Comparison among glycosaminoglycan binding cell penetrating peptides    55
Heparan sulfate-binding cell penetrating peptide for tumor targeting strategy    57
Recognition efficacy of anti-HS antibody (10E4) and GBPECP on diverse HSPG    59
Influence of sequence composition on GBP functionality    60
Direct translocation and lysosomal escape of GBP    61
Conclusion    63
Chapter 5  Reference    65
Chapter 6  Publication list    86
Journal articles    86
Conference posters    86
Patents    93

                                

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