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研究生:張淳湲
研究生(外文):Chun-Yuan Chang
論文名稱:雙劑量錸-188奈米核醫藥物處理人類癌症細胞與其腫瘤相關分子變化之探討
論文名稱(外文):Evaluation of therapeutic efficacy and tumor related molecular changes using a dual-dose of Rhenium-188 embedded liposome for cancer treatment
指導教授:李易展
指導教授(外文):Yi-Jang Lee
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物醫學影像暨放射科學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2018
畢業學年度:107
語文別:英文
論文頁數:86
中文關鍵詞:錸-188 微脂體奈米藥物人類頭頸癌上皮間質轉化切絲蛋白微核醣核酸
外文關鍵詞:188Re-liposomeHNSCCEMTCFL-1microRNA
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衛福部統計指出,頭頸癌為台灣惡性腫瘤中排名第四位,臨床上手術切除惡性腫瘤為最有效的治療方式,顏面部頭頸癌則常再以化學治療或是放射治療輔助,但因腫瘤所處位置近顱骨及血管神經的分布,切除手術需考量病患生活品質而因此受限。錸-188 微脂體藥物衰變產生貝他粒子及伽馬射線,經聚乙二醇化(polyethylene glycol, PEG)修飾後,可延長藥物體內循環時間並藉由滲透及停滯增強效應(enhanced permeability and retention, EPR) 使病灶積聚效果提升,已知錸-188 微脂體藥物可在頭頸癌小鼠模式中造成短期抑癌效應。但其生物詳細機制仍有待研究。腫瘤細胞生長及轉移過程中,切絲蛋白被廣為討論,目前雖知其為一種廣泛分布的肌動蛋白連結蛋白(actin-binding protein),在細胞骨架調控、細胞形狀維持、移動中已有許多文獻研究,但其詳細機制仍不清楚,在此研究中我們也將探討切絲蛋白於癌症中扮演的角色。
我們首先利用帶有三重報導基因之人類頭頸癌細胞株建立原位小鼠模式,分析評估雙次劑量之錸-188微脂體藥物於小鼠體內分佈積聚情形,並評估腫瘤治療效果,分析治療前後腫瘤組織腫瘤惡性程度標記蛋白變化,並一併觀察腫瘤治療前後以及細胞老化過程中切絲蛋白的表現改變。
實驗結果發現,雙次劑量治療之錸-188 微脂體藥物於小鼠腫瘤病灶處有更佳的積聚,並達到更好抑制癌症生長的效果、小鼠平均存活天數也有顯著性差異。錸-188 微脂體藥物治療後一個月的腫瘤組織中腫瘤細胞增殖因子Ki-67有明顯下降趨勢,其他上皮間質轉化標的如ZEB-1, Slug, Twist等分子於藥物處理後表現量降低,且細胞間結合蛋白E-cadherin表現量在治療後腫瘤組織中明顯上升。經高通量基因微陣列分析後發現,被視為致癌微核醣核酸如microRNA 17, 20b, 182, 196b等微核糖核酸在治療後呈下降趨勢;microRNA 206, 425*, 520f, 521等被視為抑癌角色之微核醣核酸在治療後呈上升趨勢。另一方面,我們發現在治療後切絲蛋白與p53表現量皆呈現下降趨勢,且治療後E-cadherin表現量明顯上升,可推測治療後腫瘤細胞惡性程度下降,由於先前研究已指出切絲蛋白表現量可能與老化有所關聯,而老化又為癌症危險因子之一,因此在第二章節中我們進一步討論切絲蛋白於老化與癌症中之角色。
我們首先比較不同種癌症與肺纖維母細胞中切絲蛋白表現量差異,在乳癌、肺癌、膀胱癌細胞中皆可觀察到切絲蛋白之表現量,經誘導切絲蛋白於肺癌細胞株(H1299)表現量增加後能促使細胞老化,且於肺纖維母細胞中發現切絲蛋白隨細胞代數增加上升、而端粒酶長度逐漸下降之趨勢,當年輕細胞中誘導切絲蛋白上升、老化細胞中抑制切絲蛋白表現時,都能觀察到老化與細胞生長速率受到影響,我們也發現80週齡小鼠肺、腦、腎臟組織中切絲蛋白表現量較6周齡小鼠高,於人類肺癌組織陣列中也可觀察到切絲蛋白表現量與年紀相關,利用數據資料庫分析臨床肺癌與乳癌病患發現於此兩種癌症中當切絲蛋白表現量較高時預後較差。
綜合上述,我們的研究結果首次發現雙次劑量治療可於人類頭頸癌小鼠模式中有更佳療效且可能透過微核糖核酸與上皮間質轉化的調控來達到抑制癌症細胞生長的效果,未來可透過調控特定微核糖核酸方式來確認是否會影響錸-188 微脂體藥物於腫瘤治療效應的影響,並可提供以核醫藥物為基礎的腫瘤治療兼具診斷的臨床策略。除此之外,可利用切絲蛋白進一步研究臨床上是否藉由調控與觀察切絲蛋白表現量可作為評估臨床上接受放射線治療病患之預後情形,並研究是否可利用調控切絲蛋白表現量藥物來影響腫瘤細胞說敏感度,作為日後臨床治療的預後,及精準化治療的基礎。
According to the Ministry of Health and Welfare annual cancer registration report, head and neck squamous cell carcinoma (HNSCC) is ranked as top fifth of Taiwanese malignant tumor incidence in recent statistical analysis. Surgical resection is one of the most commonly used strategies that have been performed to treat human cancers, but the surgical process is greatly restricted by the anatomical barriers, such as skull base bones and vessels. 188Re-liposome can emit both high-energy beta particles and gamma-rays, and accumulate in tumors via the enhanced permeability and retention (EPR) effect for theranostic efficacy in various human cancers. However, whether the therapeutic efficacy of 188Re-liposome is directly related to gene regulation and specific signaling pathways are largely unknown. Dual administration of radiopharmaceuticals has been investigated in treating the advanced stage of human disease. In this study, we compared the effects of a single dose and dual doses of polyethylene glycol (PEG) decorated liposome encapsulated 188Re (188Re-liposome) on human head and neck squamous cell carcinoma (HNSCC) using the orthotopic tumor model. In addition, we further investigated whether the inhibitory effects of 188Re-liposome on HNSCC were associated with microRNAs. Human hypopharyngeal FaDu carcinoma cells expressing a luciferase reporter gene were used to establish the orthotopic tumor model via buccal injection. 188Re-liposome was manufactured by conjugating 188Re and N,N-bis(2-mercaptoethyl)-N9,N9-diethylethylenediamine (BMEDA) followed by embedding into the PEGylated liposome. Cerenkov luminescence imaging (CLI) was performed to assess the tumor accumulation of 188Re-liposome after a single or dual intravenous injections. The therapeutic efficacy was determined by measuring tumor growth rate, animal survival rate and tumor markers expression. The toxicity of 188Re-liposome was evaluated by body weight and blood counts of tumor-bearing mice after treatment. Accumulation of 188Re-liposome in various organs was determined by the biodistribution, and internal doses were calculated using the OLINDA/EXM software. The pharmacokinetics of 188Re-liposome was analyzed using the WinNolin software. The microRNA profiles were detected with microRNA open array. SA-β-gal staining was used to evaluate the level of cellular senescence in cells. CLI revealed that accumulation of 188Re-liposome in tumors was increased by repeated doses compared to a single dose. Dual doses also enhanced the tumor suppression effect and elongated the survival of tumor-bearing mice. However, dual doses of 188Re-liposome showed stronger effects on decline of blood counts than the single dose group, but not on the change of body weights. Furthermore, the circulation time of 188Re-liposome was longer using dual doses. Biodistribution analysis revealed an increased accumulation of 188Re-liposome in bone marrow and tumor after dual injections. The dosimetric estimation showed that the ratio of absorbed doses for 1g tumor treated with dual doses and a single dose was about 2. The effective doses of a single dose and dual doses of 188Re-liposome were 0.177mSv/MBq and 0.245mSv/MBq, respectively. MicroRNA array results showed that several tumor proliferation-related microRNAs changed after the treatment of 188Re-liposome. Among them, microRNA-182, a biomarker that has related to HNSCC, decreased obviously in 188Re-liposome treated tumors. These effects were associated with Ki-67 proliferative marker and EMT related markers that were better inhibited in tumors treated with dual doses. Interestingly, cofilin-1(CFL-1), belongs to the actin de-polymerization factor (ADF)/cofilin family, was decreased after being treated with 188Re-liposome. We further found that the protein level of CFL-1 was higher in senescent cells. Furthermore, the same phenomenon was exhibited in both old mice tissues in different organs and lung cancer patients from commercial tissue array. Expression of higher CFL-1 leads to worse overall survival in lung cancer and breast cancer. Taken, together, current data suggest that dual-dose therapy of 188Re-liposome provides enhanced internal circulation, tumor suppression and survival extension compared to a single administration in the HNSCC tumor model. In addition, the expression of CFL-1 in cancers may be a potential biomarker for evaluating the prognosis of radiotherapy. The results of this study would provide the fundamental molecular bioinformatics for prognosis of clinical applications and personalized medicine in the future.
Table of contents
Acknowledgment………………………………………………………………………………...…………….i
Chinese abstract…………………………………..………………………..…………………………………ii
English abstract…………………………………..………………………..…………………………………iv
Table of contents…………………………………...……………………………………………………..…vi
Contents of figures………………………………..…..…………………………………………………...ix
Contents of tables and appendices…..……………..…………………..……………………….…xi
List of abbreviations…………………………………..…….....................………………………...xii
Chapter1
1. Introduction
1.1 Head and neck squamous cell cancer (HNSCC)………………………..……………….1
1.2 Liposomal drug delivery system and EPR effect…………………………………………1
1.3 Characteristic of radiophamaceuticals………………………..………………………...….2
1.4 The role of EMT in tumor metastasis…………………………………………………...…...3
1.5 The role of microRNA in cancer treatment…………………………………………..…….4
1.6 The correlation of p53 and CFL in radiotherapy in HNSCC……………………..…5
1.7 Aims of this study………………….........………………………………...…..………………..…5
2. Materials and methods
2.1 Cell lines and cell counts……………….....……………………………...…..…………………6
2.2 lentiviral infection of reporter genes…………….………………………………...…………7
2.3 Reporter genes functional assays……………………………………………...…..………...7
2.4 Preparation of 188Re-BMEDA and 188Re-liposome……………………….....….....8
2.5 Establishment of HNSCC orthotopic tumor model…………………………….........9
2.6 Protein Extraction and Western blotting……………...……………………...…..……..10
2.7 Evaluation of tumor uptake and therapeutic efficacy of 188Re-liposome in tumor-bearing mice……………………………………….........…………............................….10
2.8 Immunohistochemical (IHC) staining……………………………………...……….……….11
2.9 Measurement of blood cell counts………………………………………...………....…...12
2.10 Pharmacokinetic analysis………………………………………...…..………......……………13
2.11 Biodistribution Analysis………………………………………...…..………….......…..………13
2.12 Dosimetric evaluation of 188Re-liposomal Absorbed Dose in Vivo…………..14
2.13 MicroRNA analysis…………………………………..........……...…..………………………….14
2.14 Statistical analysis………………………………………...…..…........………………………...14


3. Results
3.1 Establishment and Validation of FaDu3R cells and reporter imaging for tracking the tumor cells in vitro and in vivo..………………………………………...…..…...15
3.2 Killing effects of 188Re-liposome on different HNSCC cell line…………...…16
3.3 Effects of a single dose and dual doses of 188Re-liposome on tumor targeting..............................................………………………………………………………......17
3.4 Comparison of therapeutic efficacy between single injection and dual treatments of 188Re-liposome on HNSCC animal model…………………....……....…17
3.5 Effects of 188Re-liposome on expression of markers for proliferation and EMT using a single dose or dual doses………………………………………...…..…………...18
3.6 Comparison of toxic effects in tumor-bearing mice treated with a single dose and dual doses of 188Re-liposome…………….....................................……….18
3.7 Comparison of biodistribution and pharmacokinetics in tumor-bearing mice treated with a single dose and dual doses of 188Re-liposome…….........…19
3.8 Dosimetric analysis for a single dose and repeated doses of 188Re-liposome administrating in the HNSCC tumor model…………..........................…..19
3.9 MicroRNA analysis of potential targets induced by 188Re-liposome…….…20
3.10 Tumor suppressive effect induced by 188Re-liposome is associated with p53 and CFL-1 expression in human HNSCC tumor-bearing mice……................21
4. Discussion…………………………………………………………………….........…………………22
5. Conclusion………………………………………………….........……………………………………27
6. Figures…………………………………………………………..........………………………………..28
7. Tables…………………………………………….……………………..........………………………...47
Chapter2
1. Introduction
1.1 CFL-1 and cellular senescence………………………………....…………………………….51
1.2 Cancer and cellular senescence……………………..……………..…………………….…52
1.3 Aims of this study…………………………………………………..........……………………….52
2. Materials and methods
2.1 Cell lines……………………………………………………….................53
2.2 Senescence-associated-β-Galactosidase (SA-β-gal) staining……..……...53
2.3 Two-dimensional gel immunoblotting analysis………………................………54
2.4 Cell growth assay……………………………………………………………..........………..…54
2.5 Telomere length assay……………………………………………………….......…………...55
3. Results
3.1 Examination the protein level of CFL-1 in both cancer and non-cancer cell lines………………………………………………………….......…………………………………………......55
3.2 Manipulation CFL-1 level could induce cell senescence in lung cancer cell line……………………………………………………….......…………………………………………………..56
3.3 Effects of cellular senescence in old WI-38 cells……….............................56
3.4 Examination the expression of CFL-1 in vivo and in Clinics….................…57
4. Conclusion……………………………………………………………….……….......……………...58
5. Figures…………………………………………………………………………………..........………..59

Appendices……………………………………………………………........................……………....69
References……………………………………………………………………..........................……….73
Publication list………………………………………………………….......................……………...83
Awards……..……………………………………………………………...........................…………….84

Contents of Figures
Figure 1 Establishment of FaDu-3R cells and Reporter gene imaging for tracking the growth of human HNSCC in xenograft tumor model………..………….28
Figure 2 The flow chart for preparation of 188Re-liposome………………........…..29
Figure 3 Preparation of 188Re based radiopharmaceutical drug…………….....…30
Figure 4 The experimental scheme for 188Re-liposome treatment in human HNSCC tumor-bearing mice model……….........................................…………………31
Figure 5 Change of cell morphology and amount in FaDu cells, SAS cells, and OECM-1 cells treated with different dosages of 188Re-liposome……................32
Figure 6 Comparison of PEGylated 188Re-liposomal accumulation in orthotopic HNSCC tumors after a single and dual injections……………..........................…….33
Figure 7 To determine the uptake of 188Re-liposome by CLI imaging……….….34
Figure 8 The tumor suppressive effect was validated by the BLI investigation35
Figure 9 Monitoring the tumor growth after treatment of a single and dual doses of 188Re-liposome……………............................................………………………36
Figure 10 Evaluation of therapeutic efficacy of a single and repeated doses of 188Re-liposome in HNSCC tumor-bearing mice model……………..................…...37
Figure 11 Effects of 188Re-liposome on the expression of molecular markers involved in cell proliferation and metastasis……………………...................…………...38
Figure 12 Effects of 188Re-liposome on the expression of EMT related markers......………………......…………...................…………………............................…..39
Figure 13 Measurement of body weights after treatment……………………....……...40
Figure 14 Effect of 188Re-liposome on blood cells in tumor-bearing mice after treatment………………………...................…………………...................…………………....….41
Figure 15 Biodistribution of single dose and repeated doses…………………………..42
Figure 16 Comparison of tumor-to-muscle ratios between a single dose and dual doses of 188Re-liposomal injection at different time points…………..……....43
Figure 17 Pharmacokinetic analysis in the human HNSCC tumor-bearing mice44
Figure 18 Analysis from MicroRNA open array………………………………………………45
Figure 19 Treatment of 188Re-liposome decreased the expression of CFL-1 and p53 in tumors………..........…………………...................………….....................……46
Figure 20 To examine the expression of CFL-1 in different types of cancer and normal cell lines…………………...................…………………...................…………………..59
Figure 21 Over-expression of CFL-1 could promote cell senescence and cause a defect in cell proliferation in H1299/tet-on-cofilin-1 cells…………………………....60
Figure 22 To compare the phenotype of young and old cells SA-β-gal staining for young cells and old cells………………….................................………………………..61
Figure 23 Evaluation of CFL-1 and p-CFL in WI-38 cells………...................………62
Figure 24 Manipulation of CFL-1 expression could regulate cell senescence and cell growth in WI-38 cells………......................................………………………………...63
Figure 25 Up-regulation of CFL-1 and p27Kip1 in aged mouse tissues…………...64
Figure 26 The expression of CFL and morphology of alveoli in young and old lung tissues from mice……………........................................……………………………...65
Figure 27 To examine the level of CFL-1 in paraffin-embedded human lung cancer tissue array...………………...................…………………...................….............66
Figure 28 Associations of CFL-1 expression with overall survival in lung cancer via KM plotter database from clinical lung cancer patients………………………..……67
Figure 29 Associations of CFL-1 expression with overall survival in breast cancer via KM plotter database from clinical breast cancer patients…………….……………68



Contents of Tables and Appendices
Tables

Table 1 Pharmacokinetic analysis for single dose and dual-dose of 188Re-liposome treatment on HNSCC tumor-bearing mice……………...............……………47
Table 2 Radioactivity distribution in tumor and other organs of FaDu-3R tumor-bearing mice after intravenous injection of 188Re-liposome……............48
Table 3 Dosimetric estimation of a single dose and dual doses of 188Re-liposome in human organs according to the results of biodistribution analysis in tumor-bearing mice…………………………………….…………………….……………....…………..49
Table 4 Dosimetric estimation of absorbed dose in tumor sphere mode.......l50

Appendices

Appendix 1. Change of Cerenkov luminescent signals between first injection and second injection of 188Re-liposome to tumor-bearing mice.……………………69
Appendix 2. Analysis of potential KEGG pathway induced by 188Re-liposome…………………….…………………….…………………….…………………….………………..70
Appendix 3. Imaging of 18F-FDG and 18F-FLT in PDX mice model………...……71
Appendix 4. List of antibodies………………………..………………………………….…………71
Appendix 5. Establishment of multiple reporter genes (pLT-3R construct)....72
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