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系統識別號 U0026-1807201316285200
論文名稱(中文) 研究PLGA奈米粒子包裹小分子抑制藥物增強細胞死亡相關之機轉
論文名稱(英文) Study the mechanisms underlying the cell death enhancement by loading small molecule inhibitors into PLGA nanoparticles
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 侯佳成
研究生(英文) Chia-Cheng Hou
學號 s58951120
學位類別 博士
語文別 英文
論文頁數 119頁
口試委員 指導教授-蘇五洲
指導教授-謝達斌
召集委員-蔣輯武
口試委員-葉晨聖
口試委員-洪文俊
口試委員-謝興邦
中文關鍵字 2-嗎啉-4-基-8-苯基-4H-色烯-4-酮  無表面活性劑聚乳酸聚乙醇酸共聚物  內質網壓力  含纈酪肽蛋白 
英文關鍵字 LY294002  surfactant-free PLGA  ER stress  VCP 
學科別分類
中文摘要 LY294002 (LY, 2-嗎啉-4-基-8-苯基-4H-色烯-4-酮)是一種有效抑制磷脂醯肌醇3-激酶(phosphatidylinositol 3-kinases, PI3Ks)的小分子抑制劑,但是,微水溶性與低劣的藥物代謝動力學特性則是侷限LY在生物體上的應用。聚乳酸聚乙醇酸共聚物(poly(lactic-co-glycolic acid), PLGA)是一種可生物降解的奈米材料,可以用來作為載體用於藥物傳遞。 因此,我們發展出LY294002包覆於無表面活性劑的PLGA奈米粒子(LY294002-loaded surfactant-free PLGA nanoparticles, SF-LY NPs)並研究是否該奈米粒子可以改善LY的療效。 SF-LY NPs,相較於LY294002包覆於表面活性劑聚乙烯醇(polyvinyl alcohol, PVA) 的奈米粒子(LY294002-loaded PVA -containing PLGA nanoparticles, PVA-LY NPs) 以及 LY,則表現出優越的抑制細胞生長效果、持續抑制絲氨酸/蘇氨酸激酶 (蛋白激酶B) (protein kinase B, AKT)的活性以及增加LY在細胞內的含量。此外,我們觀察到SF-LY NPs傾向於積累在內質網 (endoplasmic reticulum, ER),並誘發顯著的內質網壓力(ER stress)反應所衍生的細胞死亡機制。將SF-LY NPs注射到腫瘤後也表現抗腫瘤的作用。在SF-LY NPs誘導的細胞死亡機制,我們建立了能定位在不同胞器中的PLGA奈米粒子,並發現到位於內質網中的SF-LY NPs能促使細胞死亡。此外,我們也觀察到諸多現象,如,內質網衍生空泡化 (ER-derived vacuolization) 和泛素高度聚集的聚集小體 (aggresomes)。接下來,我們發現含纈酪肽蛋白(Valosin-containing protein, VCP)是重要的因子,其能減緩SF-LY NPs誘導的諸多細胞現象和細胞死亡。這些研究結果表明,SF-LY NPs通過PI3K/AKT和VCP相關機制導致細胞死亡並具有發展成抗癌藥物的潛力。
英文摘要 LY294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, bio-applications of LY are limited by its poor solubility and pharmacokinetic profile. Poly (lactic-co-glycolic acid) (PLGA) is a biodegradable nanomaterial that can be used as a carrier for drug delivery. LY294002-loaded surfactant-free PLGA nanoparticles (SF-LY NPs) were developed to improve the therapeutic efficacy of LY. SF-LY NPs showed a stronger growth inhibitory effect, sustained suppression of the serine/threonine kinase AKT activation, and increased intracellular uptake of LY compared with LY294002-loaded PVA (polyvinyl alcohol) -containing PLGA nanoparticles (PVA-LY NPs) or free LY. In addition, we observed that SF-LY NPs tend to accumulate in the endoplasmic reticulum (ER), subsequently induced pronounced ER stress-derived cell death. After injection into tumors, SF-LY NPs exhibited a stronger antitumor effect than free LY. In cell death mechanisms of SF-LY NPs, we developed different organelle-targeting PLGA NPs with LY entrapment and found that SF-LY NPs preferentially located at ER to determine cell fate, rather than the properties of PLGA NPs. Furthermore, PLGA NPs with LY loading, located at ER, exhibited multiple cellular phenomena, such as, ER-derived vacuolization and ubiquitin-concentrated aggresomes. Next, we identified that vasolin-containing protein (VCP) rescued SF-LY NPs -induced multiple cellular phenomena and was critical for SF-LY NPs -mediated cell death. These findings indicated that the surfactant-free formulation of PLGA is an ideal vector to carry LY and that SF-LY NPs possess promising anticancer activity via both PI3K/AKT and VCP -related mechanisms.
論文目次 中文摘要 I
Abstract III
致謝 V
Contents VI
Abbreviation list XI
Chapter 1:Introduction 1
1-1 The nanotechnology 2
1-2 Characteristics of polymers 2
1-3 The characteristics of polyesters (PLA, PGA and PLGA) 4
1-4 Physico-chemical and biological properties of PLGA 5
1-4-1 Physico-chemical properties 5
1-4-2 Biological properties 6
1-5 The encapsulation technologies of PLGA 6
1-5-1 Solvent evaporation 7
1-5-2 Phase separation (coacervation) 9
1-5-3 Spray drying 9
1-6 PLGA delivery systems 10
1-6-1 Passive targeting 10
1-6-2 Active targeting 11
1-6-3 Intracellular target 11
1-7 The hallmarks of cancer 12
1-8 PI3Ks family classifications 13
1-8-1 Class I PI3Ks 13
1-8-2 Class II PI3Ks 14
1-8-3 Class III PI3K 14
1-9 The importance of PI3K pathways 15
1-10 The role of small molecular inhibitor, LY294002, in the PI3K pathway 16
1-11 Rationales 17
1-12 Specific aims 19
1-12-1 To investigate whether surfactant-free PLGA nanoparticles against PI3K signaling have excellent property for tumor suppression 19
1-12-2 To investigate whether surfactant-free PLGA nanoparticles against PI3K signaling resulted in cell death via organelle-targeted mechanisms 20
Chapter 2: Materials and Methods 21
2-1 Materials 22
2-1-1 Drugs and reagents 22
2-1-2 Antibodies 22
2-1-3 Cell lines 23
2-2 Methods 24
2-2-1 Cell culture 24
2-2-2 Preparation of surfactant-free PLGA nanoparticles 24
2-2-3 Conjugation of CD44 antibody to PLGA NPs 25
2-2-4 Encapsulation capacity measurement 25
2-2-5 Transmission electron microscopy (TEM) of the nanoparticles 26
2-2-6 In vitro PI3Ks inhibitors release studies 26
2-2-7 MTT Cytotoxicity assay 27
2-2-8 Immunofluorescence and confocal microscopy 27
2-2-9 Western blot analysis 28
2-2-10 FACS analysis 29
2-2-11 DAPI staining for chromosome condensation 29
2-2-12 Design and transfection of small interfering RNA (siRNA) 30
2-2-13 Quantitative analysis of intracellular LY or Nile red in nucleus-cytoplasm distribution 30
2-2-14 Tumor xenograft experiments 31
2-2-15 Clarified detergent-insoluble fractions 32
2-2-16 Immunoprecipitation 32
2-2-17 Statistical Analysis 32
Chapter 3: Result 34
3-1 To investigate whether surfactant-free PLGA nanoparticles against PI3K signaling have excellent property for tumor suppression 35
3-1-1 Surfactant-free PLGA nanopartilce characterization 35
3-1-2 The cytotoxicity of SF-LY NPs was better than that of free LY or PVA-LY NPs 36
3-1-3 SF-LY NPs -mediated cytotoxicity was via instrinic apoptotic pathways 37
3-1-4 SF-LY NPs affected the levels of AKT phosphorylation 38
3-1-5 The unique internalization and localization of SF-LY NPs 39
3-1-6 SF-LY NPs induced ER stress and ER stress-related apoptosis 40
3-1-7 In vivo study 42
3-2 To investigate whether surfactant-free PLGA nanoparticles against PI3K signaling resulted in cell death via organelle-targeted mechanisms 43
3-2-1 The CD44 ligand -conjugated PLGA nanoparticles were internalized and delivered to nucleus 43
3-2-2 The different cytotoxicity and ER stress response depended on the localization of SF NPs, not the properties of NPs 44
3-2-3 SF-LY NPs induced ER-derived vacuolization and expansion 46
3-2-4 SF-LY NPs resulted in ubiquitinated proteins aggregation at the ER through VCP inactivation 48
3-2-5 VCP is the key factor for SF-LY NPs -mediated cell death and ER stress response 50
Chapter 4: Discussion and Conclusion 52
References 65
Tables and Figures 80
Table 1. The properties of nanoparticles and chemical compound in this study 80
Figure 1. Characterization of SF-LY NPs 82
Figure 2. Cytotoxic effects of SF-LY NPs determined by MTT assay 83
Figure 3. The level of apoptosis and chromatin condensation by SF-LY NPs 85
Figure 4. The effect of cytochrome C and caspase activity by SF-LY NPs 87
Figure 5. The level of activated AKT by SF-LY NPs 89
Figure 6. The intracellular incorporation of PLGA NPs in cancer cell lines 91
Figure 7. The intracellular localization of PLGA NPs in cancer cell lines 92
Figure 8. The effect of ER stress status 94
Figure 9. The effect of cytotoxicity on SF-LY NPs -mediated ER stress 96
Figure 10. The regulation of autophagy after treatment with free LY or SF-LY NPs 98
Figure 11. The effect of intratumoral injection in vivo 100
Figure 12. The intracellular localization of ADVNLS-conjugated PLGA NPs 102
Figure 13. The intracellular localization of CD44-conjugated PLGA NPs 103
Figure 14. Quantitative analysis the uptake of nanoparticle formulations in nucleus-cytoplasm fraction 104
Figure 15. The regulation of cytotoxic effects and signaling pathways of SF-LY NPs or CD44-LY NPs 105
Figure 16. Characterization of the ligane-conjugated nanoparticle formulations 107
Figure 17. The level of intracellular incorporation of SF NPs or CD44 NPs 109
Figure 18. The ER-derived vacuolization in response to SF-LY NPs 110
Figure 19. The ubiquitinated proteins aggregation in response to SF-LY NPs 112
Figure 20 The regulation of VCP in response to SF-LY NPs 114
Figure 21 The mechanisms of cell death enhancement in response to SF-LY NPs 116
Figure 22 The outcome of SF-LY NPs –mediated cell death enhancement 118
作者簡歷 119
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