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系統識別號 U0026-0502201304302400
論文名稱(中文) 藉由PLGA奈米載體改善對抗STAT3的策略
論文名稱(英文) Using PLGA nanoparticle as a carrier to improve anti-Stat3 strategy.
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 1
出版年 102
研究生(中文) 葉上瑜
研究生(英文) Shang-Yu Yeh
學號 T16991062
學位類別 碩士
語文別 英文
論文頁數 57頁
口試委員 指導教授-蘇五洲
召集委員-蔣輯武
口試委員-張俊彥
中文關鍵字 聚乳酸甘醇酸  奈米載體  奈米抗癌藥物 
英文關鍵字 STAT3  PLGA  nanoparticle  PP2A  AG490  S3I201  FTY720 
學科別分類
中文摘要 根據先前的研究指出,在許多人類惡性腫瘤中,STAT3轉錄因子會受到細胞激素、生長因子及賀爾蒙的誘導而引發持續性的活化,並參與調節一系列關於血管新生、細胞週期進行、細胞遷移及免疫反應的相關機制。除了直接表現在癌細胞中,持續活化的STAT3也表現在腫瘤鄰近間質組織的免疫細胞、基質細胞及內皮細胞中。而白細胞介素6 (IL-6)及其受器gp130蛋白,自泌/旁泌調控的細胞轉型及增生及下游JAK-STAT3訊息傳遞路徑的異常活化已被認定與腫瘤的生成有很大的相關性。因此,我們運用AG490,JAK2/EGFR的抑制劑,藉由抑制gp130蛋白的生成、JAK蛋白的活化,使經由白介素6誘導的STAT3也得以受到控制;另外, S3I201,為STAT3蛋白活化進入細胞核作用時必須形成的同源二聚體的競爭物,使STAT3蛋白無法形成二聚體,藉此阻斷STAT3蛋白活化和下游訊息的傳遞。
我們更嘗試使用具有生物相容性、分解性、無毒性、在水溶液中具高度分散性的聚乳酸甘醇酸 (PLGA)聚合物材質,利用『乳化法』、『奈米沉澱法』,高分子穩定劑的有無,將藥物AG490、S3I20、或兩者一起,包裹在其中使形成穩定、可緩慢降解並持續釋放藥物的奈米粒子,也藉由奈米粒子特性增加藥物吸收率、降低藥物副作用,期待達到藥物的最佳效果。以奈米沉澱法包裹藥物後發現,由於未加入高分子穩定劑,奈米粒子表面未被聚乙烯醇所包覆,造成藥物離心濃縮時容易集結成團無法回復成穩定藥物,受限於此,藥物處理細胞的效果必然受到了濃度有所限制的牽制。經由奈米沉澱法包覆後的藥物濃度: AG490為39.2~47.6uM、S3I201為8.9~14uM、若兩者一起相互影響則AG490 13.4~15.8uM + S3I201 3.84~14uM,於是再加入2%小牛血清蛋白填補奈米粒子表面不平滑處,使藥物可以濃縮。
在PC14PE6/AS2 (AS2)、H1299、H460、CL1-5、CL1-0細胞中STAT3-p (Y705)及AKT-p (S473),可受到未經包裹、較高濃度約150uM AG490的抑制,而ERK-p則無明顯變化或是反而更加活化,顯示出細胞中由不同蛋白所調控的訊息傳遞路徑的複雜度。經奈米沉澱法包裹後的AG490,在H460細胞中,約40.6uM的藥物濃度即可有明顯的抑制效果;使用乳化法包裹的AG490,則在與未經包裹的藥物比較之下有些許的抑制效果。此結果引導出: 經由乳化法及奈米沉澱法的藥物包裹方式皆有成效,但是否造成藥物在細胞中的傳遞路徑、降解效率的不同,還有待往後更進一步的研究。
S3I201藥物的藥效則因細胞的不同有顯著的特異性: 在H1299細胞中未經包裹的S3I201在50uM濃度即有明顯誘導細胞凋亡效果,用奈米沉澱法與AG490一起包覆後的S3I201在20uM即有藥效;但在LL2細胞中,未經包裹的20uM及利用乳化法包裹的 S3I201則反而誘發JAK2-p、STAT3-p、AKT-p、ERK-p的活化。所以為了在普遍細胞中皆能觀察到藥物包裹前後效用的比較,另增加了FTY720藥物,為神經醯胺類似物,與影響JAK2誘導白介素6、STAT3持續活化的Sphingosine-1-phosphate (S1P)為競爭者,進一步阻斷JAK-STAT訊息路徑,達到抑制腫瘤的效果。經由乳化法包覆後的FTY720,在不同細胞株之間的STAT3相關訊息路徑皆有不錯的抑制效果,由此引發出: 是否為STAT3活化阻斷劑也為PP2A促進劑的FTY720,也同時導致細胞中PP2A不同B次單元的調控,進一步促使腫瘤細胞凋亡。從這些實驗結果我們了解到不同癌細胞株所仰賴逃避細胞凋亡的訊息傳遞路徑,也期望能更進一步的發展出具高度專一性,較高敏感度的長效型抗癌奈米藥物。
英文摘要 According to the previous researches, Constitutive signal transducer and activator of transcription3 (STAT3) would be activated persistently by cytokines,growth factors and hormones, to be involved in angiogenesis, cell cycle regulation, cell metastasis and immune response in plenty of human malignant tumors . In addition to tumor cells, activated STAT3 is also found in immune cells, stromal cells and endothelial cells of tumor microenvironment. The autocrine/paracrine Interleukin-6 and the receptor gp130 induced aberrant downstream JAK-STAT3 signaling pathway activation that is responsible to cell transformation and proliferation has been identified in connection with tumorgenesis. Therefore, we used AG490, JAK2/EGFR inhibitor, to downregulate gp130 and JAK proteins and control the activation of STAT3. Furthermore, S3I201 (NSC-74859), the STAT3 dimerization inhibitor, dockes to the SH2 domain of STAT3 and inhibits dimer complex formation, the DNA-binding and transcriptional activities.
We encapsulated AG490, S3I201, and combination of them into Poly (D, L-lactide-co-glycolide) (PLGA) polymers , are biocompatible, biodegradable and non-toxic, by “single emulsion solvent evaporation method” or “nanoprecipitaion” to form nanoparticles (NPs), which retains intracellularly could release the encapsulated drug slowly, raises drug sensitivity and side effects, leading to a sustained drug effect. In the result of surfactant-free nanoprecipitaion method, the NPs were aggregated and cannot be dissolved in medium after centrifugation, so the drug treatments of cell lines would be limited by the drug concentration. The concentration of drugs by nanoprecipitaion: AG490, 39.2~47.6uM; S3I201, 8.9~14uM; the combination of AG490 and S3I201, 13.4~15.8uM and 3.84~14uM. We then added 2% bovine serum albumin (BSA) to fill the unsmooth on NPs surface and concentrate the drugs.
The expression of STAT3-p (Y705) and AKT-p (S473) in PC14PE6/AS2 (AS2)、H1299、H460、CL1-5、CL1-0 cell lines were downregulated by free form at high dose (~150uM) AG490; ERK-p had no significant change or activated instead. It shows the multilevel cross-talk among targets of several signaling pathways. In H460 cell lines, the AG490 NPs encapsulated by nanoprecipitaion had an obviously depression effect on target proteins at 40.6uM; on the other hand, the single emulsion solvent evaporation products had less effect at the higher dose compared to free form drug. These results indicated that the systems of NPs formation may affect the transmission pathway and degradation rate in cells, which should be confirmed further.
The effect of S3I201 has different specificity on cell lines: In H1299 cell line, the free form S3I201 induced cell apoptosis significantly at 50uM. After encapsulated with AG490 by nanoprecipitaion, the combination had considerably effect at 20uM. Otherwise, the activation of JAK2, STAT3, AKT and ERK in LL2 cell line was induced by the single emulsion solvent evaporation NPs. To compare the drug efficiency in general cell lines, the ceramid mimick, FTY720 would compete with Sphingosine-1-phosphate (S1P) to block the IL6-relate JAK-STAT signaling pathway. The single emulsion solvent evaporation FTY720 NPs had effect on STAT3-associated signaling pathways. These data indicated that FTY720 functions as the blocker of JAK-STAT pathway and, FTY720 also induces activation of PP2A by regulating the different B subunits and promots the apoptosis of tumor cells.
Form the result of experiments, we realized the potential signaling pathways cells may rely on to escape from cell death. We also expect to develop ideal nanodevices which can effectively suppress central pathways in cancer cells and cells of tumor microenvironment with significant effects.
論文目次 Table of Contents
Abstract in Chinese… І
Abstract in English … Ш
Abbreviation list … VІ
Acknowledgments … VІІ
Index … VШ
List of Tables … X
List of Figures… ХІ
List of Attachments … ХІІ

1. Introduction … 1
1.1 The STATs family and the JAK-STAT signaling pathway 1
1.2 The physiological functions of STAT3 2
1.3 STAT3 and cancer 3
1.4 Protein Phosphatase 2A / PP2A 4
1.5 Protein Phosphatase 2A and cancer 5
1.6 Poly (D, L-lactic-co-glycolic acid) / PLGA 6
1.7 Reagents 7
2. Materials and Methods 9
2.1 Cell culture 9
2.2 Cell lysis and Western blotting 10
2.3 Antibodies 10
2.4 Reagents 12
2.5 Cytotoxic analysis - MTT assay 13
2.6 Preparation of PLGA nanoparticles (PLGA NPs) 13
2.6.1 Nanopricipitaion (surfactant-free system) 13
2.6.2 Single emulsion solvent evaporation method (surfactant system) 14
2.7 Drug encapsulation efficiency 15
3. Results 16
3.1 The advantages & disadvantages between surfactant-free system and surfactant system 16
3.2 The cell treatments with free form and PLGA-AG490 or S3I201 16
3.3 The cell treatments with PLGA-AG490+S3I201 18
3.4 The cell treatments with surfactant system: PLGA-FTY720 18
4. Discussion 20
5. References 32







List of Tables
Table 1. The structure and the chemical information of drugs 40
Table 2. The flowchart of nanopricipitaion (surfactant-free system) 41
Table 3. The flowchart of Single emulsion solvent evaporation method (surfactant system) 42
Table 4. The analysis of PLGA drugs without surfactant (Nanopricipitaion) 43
Table 5. The analysis of PLGA drugs with surfactant (single emulsion solvent evaporation method) 44








List of Figures
Figure 1.1 The IC50 and cytotoxic effect of AG490 exhibited in a dose-dependent pattern in PC14PE6/AS2 (AS2) cell line for 24hr and 48hr. 45
Figure 1.2 The IC50 and cytotoxic effect of AG490 exhibited in a dose-dependent pattern between CL1-0 and Cl1-5 cells in 48hr 46
Figure 1.3 The IC50 and cytotoxic effect of S3I201 exhibited in a dose-dependent pattern in AS2 line 47
Figure 1.4 The IC50 and cytotoxic effect of S3I201 exhibited in a dose-dependent pattern between CL1-0 and Cl1-5 cells in 48hr. 48
Figure 2. Figure.2 AS2 and H460 cells showed the better sensitivity to PLGA AG490 treatment. 49
Figure 3. CL1-0 cell and more invasive CL1-5 cell had the different regulate mechanism of kinases. 50
Figure 4. H1299 had the better sensitivity to S3I201 than AG490 51
Figure 5. LL2 cell had abnormal kinases phosphorylation after S3I201 treatment.
52
Figure 6. AS2 and H1299 cell were treated with the PLGA AG490 and S3I201 combination. 53
Figure 7. The PLGA-FTY720 had obviously medicine property in AS2 cell. 54
Figure 8. The human esophageal squamous cell carcinoma (ESCC) TE1 cell line transfected with pMSCV, 4HAB56γ3 or shB56γ3 system. 55


List of Attachments
Attachment A. Synthesis and Hydrolysis of PLGA polymer. 56
Attachment B. The downstream signaling pathways of IL6-JAK-STAT3. 57
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