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研究生:林亮廷
研究生(外文):Liang-Ting Lin
論文名稱:探討錸-188-奈米微脂體藥物於治療人類非小細胞肺癌及人類頭頸癌之前臨床測試與其分子抑癌機制
論文名稱(外文):Preclinical Evaluation and The Study of Tumor Suppressive Mechanism in Nanopegylated Rhenium-188-liposomal Drug Treating Human NSCLC and HNSCC
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:2014
畢業學年度:102
語文別:英文
論文頁數:98
中文關鍵詞:非小細胞肺癌頭頸部鱗狀細胞癌微脂體核醫藥物錸-188多模組分子影像藥物動力學
外文關鍵詞:NSCLCHNSCCliposomal radiopharmaceuticalrhenium-188multimodality molecular imagingpharmacokinetics
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非小細胞肺癌為一種惡性度高且致命的癌症,傳統化學治療與放射治療的效果往往相當有限。而人類頭頸部癌症有超過90%屬於鱗狀細胞癌,而由於頭頸部血管、淋巴及神經的解剖構造十分複雜,致使手術切除的難度極高,輔以放射治療是當前主要的治療方法,相較之下第一線化學治療的使用率相對較低,多針對轉移性的頭頸癌進行治療。近期,聚乙二醇化之奈米微脂體藥物已被證實可有效延長藥物於活體內的循環時間,並且藉由EPR效應使其積聚於腫瘤患部,達到治療的效果。此外,利用放射性核種標誌的藥物來治療非小細胞肺癌以及頭頸癌的相關研究仍缺乏。因此,本研究中我們將放射性核種錸-188包覆於奈米化微脂體中,並使用原位接植小鼠模式搭配多模組分子影像,針對生物體分布分析、藥物動力學以及療效評估等,做一系統分析。
為利於活體中進行長時間非侵入式的追蹤,本研究首先利用2A多肽鏈連結多個報導基因,包含綠色螢光蛋白、螢火蟲螢光酶及第一型簡單皰疹病毒胸腺激酶等。將人類非小細胞肺癌細胞株NCI-H292與人類頭頸部鱗狀細胞癌FaDu細胞株經慢病毒感染後獲得穩定表現多重報導基因之穩定細胞株,並將其接植於免疫缺失小鼠建立皮下及原位小鼠模式。另一方面,錸-188首先與N,N-bis(2-mercaptoethyl)-N',N'- diethylethylenediamine (BMEDA)接合後,將其包覆於聚乙二醇(polyethylene glycol, PEG)修飾之微脂體之中,形成錸-188-微脂體。經尾靜脈注射後,利用單光子斷層掃描追蹤,或將小鼠犧牲後進行生物體分布分析,進而量化藥物積聚與排除情況,之後並利用WinNonlin及OLINDA/EXM軟體計算藥物動力學參數與體內吸收劑量評估。另外,我們也利用光學影像追蹤並定量原位腫瘤接受錸-188-微脂體藥物治療後之療效評估。
實驗結果顯示錸-188-微脂體藥物於皮下接植NCI-H292人類非小細胞肺癌以及原位接植人類頭頸部癌症FaDu腫瘤小鼠模式中之生物體分布分析及單光子斷層掃描影像結果相符,於肝臟、脾臟以及腫瘤位置皆有顯著的藥物積聚現象;同時,藥物動力學成果顯示錸-188-微脂體相較於未包覆之錸-188-BMEDA具有明顯較長的生物體內半衰期。然而,錸-188微脂體藥物在皮下模式雖能明顯觀測積聚效應,但於原位腫瘤模式卻無法使用影像觀測,我們遂利用伽馬計數器定量後確認,並在療效評估中看見顯著的腫瘤抑制效應。荷腫瘤小鼠之生存中位數也相較於控制組有效地延長至兩倍。本研究也是首次展示錸-188-微脂體藥物於治療人類非小細胞肺癌之有效成果。
然而,在原位頭頸部腫瘤小鼠模式研究中,雖然腫瘤抑制的效果相當顯著,但在Kaplan-Meier生存曲線中發現,與控制組相比,錸-188-微脂體藥物治療組的生存中位數並沒有顯著的延長(p=0.1161)。而在免疫病理染色檢查中,我們觀察到在給藥四週後,腫瘤組織Ki67表現量與治療當週的表現量有著顯著差異,光學造影也顯示腫瘤生長在治療20日後開始快速增加,這些結果都顯示錸-188-微脂體藥物可能僅提供短暫的生長抑制功能。因此,為了解人類頭頸癌細胞在接受錸-188-微脂體藥物治療之後的分子抑癌機制,我們將腫瘤取下後萃取核醣核酸,並使用基因表現微陣列晶片分析,並經Ingenuity Pathway Analysis (IPA)與Gene Set Enrichment Analysis (GSEA)進行分析,發現微核醣核酸let-7家族在接受錸-188-微脂體治療後,在基因表現與下游基因變化量都有顯著的變化。我們進一步地利用即時定量聚合酶連鎖反應(real-time qPCR)對其相關基因進行分析。結果顯示許多與let7相關的基因也都協同變化,顯示抑癌機制的啟動,然而這些機制可能僅能維持一段時間,使得治療效果未能長期維持。
總結來說,本研究說明了聚乙二醇化錸-188-奈米微脂體藥物於荷人類非小細胞肺癌腫瘤以及荷人類頭頸部鱗狀細胞癌腫瘤小鼠之藥物動力學、生物體分布及體內劑量評估,並且證實此類奈米核醫藥物之治療具有實際療效。此研究成果也可作為未來應用錸-188-微脂體藥物於臨床使用之基礎。

Non-small cell lung cancer (NSCLC) is a high morbid and mortal cancer type that is difficult to be eradicated using conventional chemotherapy and radiotherapy. Besides, over 90% of the head and neck cancers are categorized as squamous cell cancers (HNSCC). Surgical dissection is the most effective treatment currently for both cancers. However, the locations of HNSCC limit the surgical procedures by the surrounding organs and functions. Additionally, chemotherapy is not recommended in first line HNSCC treatment but for metastatic cases, and severe side effects worsens the life quality of patients. Recently, PEGylated liposomal drugs have been characterized for the prolonged residence in tumors through the enhanced permeability and retention (EPR) effect. Little is known whether radionuclide based pharmaceutials can be used for treating NSCLC and HNSCC. Here we embedded the therapeutic radionuclide Rhenium-188 (188Re) to PEGylated liposomes and investigated the biodistribution, pharmacokinetics, and therapeutic efficacy of this radiopharmaceutical on NSCLC and HNSCC using xenograft pulmonary and hypopharyngeal mice model and the reporter gene imaging techniques.
Human NSCLC NCI-H292 and HNSCC FaDu cells expressing multiple reporter genes were used in this study. Rhenium-188 was conjugated to the N,N-bis(2-mercaptoethyl)-N',N'- diethylethylenediamine (BMEDA) and loaded into the PEGylated liposome to form 188Re-liposome. The tumor growth rates and localizations were confirmed using the bioluminescent imaging and the single photon emission computed tomography/computed tomography (SPECT/CT) after the 188Re-BMEDA or 188Re-liposome was intravenously injected. The accumulation of the nanodrug in various organs was determined by the bio-distribution analysis and the nanoSPECT/CT system. The pharmacokinetic and dosimetric analysis was further determined using the WinNonlin and OLINDA/EXM, respectively.
The biodistribution showed that PEGylated 188Re-liposome could efficiently accumulate in NSCLC tumors formed subcutaneously, as well as the orthotopic HNSCC model, in nude mice. Pharmacokinetic analysis also showed that the retention of 188Re-liposome was longer than that of 188Re-BMEDA. In orthotopic tumor model, ex vivo  counting revealed that the uptake of 188Re-liposome was detected in tumor lesion but not in surrounding normal lung tissues. Moreover, we evaluated the therapeutic efficacy using the bioluminescent imaging and showed that both NSCLC and HNSCC tumor growth was suppressed but not eradicated by 188Re-liposome. The life span of 188Re-liposome treated NSCLC-bearing mice was 2 folds longer than that of untreated control, whereas HNSCC-bearing mice were not significantly changed. Therefore, microarray was used for screening the potent tumor suppressive mechanism triggered by 188Re-liposome treatment. Interestingly, we found that let-7 microRNA family gene set was most altered by the calculation of Gene Set Enrichment Analysis (GSEA). We then concluded the Ingenuity Pathway Analysis (IPA) results, and noticed that some tumor suppressive mechanisms were activated. Suggesting that the close-range and crossfire mode of radiotherapy can effectively suppress the tumor growth.
In summary, the results of bio-distribution, pharmacokinetic, estimated dosimetry, nanoSPECT/CT, and the bioluminescent imaging suggest that the PEGylated liposomes embedded 188Re would be used for the treatment of human lung cancers. Our findings also suggest that 188Re-liposome has a great potential in treating HNSCC by triggering a tumor suppressive machinery, and the results we reported could be crucial information for further clinical use.

Table of contents

Acknowledgement…………………………………………………………………….i
Chinese Abstract………………………………………………………………………ii
English Abstract……………………………………………………….…………...iv
Table of contents……………………………………………………………………vi
Contents of Figures……………………………………………………………………ix
Contents of Tables……………………………………………………………………xi
Abbreviations…………………………………………………………………………..xii

Chapter1. The bio-distribution, pharmacokinetic, and therapeutic efficacy studies of 188Re-liposome treatment in human NSCLC mice model
1. Introduction
1.1 Non-small cell lung cancer (NSCLC)…………...……………………………..2
1.2 Liposome drug delivery system……….………………………………………..2
1.3 Multicistronic gene expression system…………...……………………………7
1.4 Reporter gene imaging……..……………………..……………………...….8
1.5 Nuclear medicine imaging…………………………………………………..10
1.6 Theranostic radiophamaceuticals………………..……………………………12
1.7 Aims of this study……………………………….…………………………….13
2. Materials and methods
2.1 Cell lines…………………………………………………………………....14
2.2 Polycistronic plasmid and lentiviral infection of reporter genes……….…14
2.3 Reporter gene function assays…………………………………………....15
2.4 Establishment of human NSCLC tumor-bearing animal model……..………..16
2.5 Preparation of 188Re-BMEDA and 188Re-liposome………………….………..17
2.6 Biodistribution and pharmacokinetic analysis……..……………………….17
2.7 Dosimetric evaluation of 188Re-liposome absorbed radiation dose in vivo...18
2.8 In vivo radionuclide based imaging and bioluminescent imaging…………18
2.9 Therapeutic efficacy evaluation………………………………………………19
2.10 Statistical analysis…………………………………………………………….20
3. Results
3.1 Expression of polycistronic reporter system in non-small cell lung cancer cell lines………………………………….……………………………..………20
3.2 The Bio-distribution and the nanoSPECT/CT imaging of 188Re-BMEDA and 188Re-liposome in human NSCLC tumor-bearing mice………………………21
3.3 Establishment of orthotopic human NSCLC tumor-bearing mice model……………………..…………………………………………………21
3.4 The pharmacokinetics of orthotopic human NSCLC NCI-H292 tumor-bearing mice……………………………………………………….…………...……...22
3.5 The estimation of absorbed radiation dose in 188Re-liposome treating regimen………………………………………………………………..………23
3.6 Therapeutic efficacy evaluation of 188Re-liposome in human NSCLC NCI-H292 tumor-bearing mice by optical imaging………...………….……..23
4. Discussion……………………………………………………………………..…25
5. Conclusion………………………………………...……………………………..29
6. Tables…………………………………………………………………….……..30
7. Figures………………………………………………………………………….33

Chapter2. The therapeutic efficacy of 188Re-liposome treatment in human HNSCC mice model and its genetic alterations after the internal radiotherapy
1. Introduction
1.1 Head and neck squamous cell cancer (HNSCC)………………………………..51
1.2 The biological role of microRNA………………………………………………52
1.3 Aims of this study………………………………………………………………53
2. Materials and Methods
2.1 Cell lines………………………………………………………………………..54
2.2 Protein Extraction and Western blotting………………………………………..54
2.3 RNA extraction and real-time quantitative polymerase chain reaction………55
2.4 Gene expression microarray analysis…………………………………………56
2.5 MicroRNA targets prediction and in silico investigation………………………57
2.6 Establishment of human HNSCC tumor-bearing animal model………………57
2.7 Paraffin-embedded section and immunohistochemistry staining………………58
2.8 Therapeutic evaluation……………………………………………………….59
2.9 Statistical analysis……………………………………………………………..59
3. Results
3.1 Establishment of orthotopic human HNSCC tumor-bearing mice model……60
3.2 The bio-distribution and pharmacokinetics of orthotopic human HNSCC FaDu tumor-bearing mice……………………………………………………………60
3.3 Therapeutic efficacy evaluation of 188Re-liposome in human HNSCC FaDu tumor-bearing mice by optical imaging………………………………………..61
3.4 The ex vivo genetic profiling in the 188Re-liposome treated tissues……………62
4. Discussion……………………………………………………….………………….63
5. Conclusion………………………………………………………………………….66
6. Tables……………………………………………………………………………….67
7. Figures……………………………………………………………………………71
References…………………………………………………………………………83
Appendix……………………………………………………………………………98

Contents of Figures
Figure 1 The scheme for the enhanced permeability and retention (EPR) effect………………… 5
Figure 2 The flow chart for the 188Re-liposome manufacture……………………………………. 33
Figure 3 Instant thin layer chromatography (iTLC) analysis…………………………………... 34
Figure 4 The scheme for the LT-3R.hyg construction…………………………………………. 35
Figure 5 The establishment of multiple reporter genes-expressing human NSCLC cell lines…… 36
Figure 6 The nanoSPECT/CT image for the detection of bio-distribution of 188Re-labeled radiopharmaceutical in vivo…………………………………………………………….. 37
Figure 7 The bio-distribution of 188Re-BMEDA and 188Re-liposome in human NSCLC tumor-bearing mice……………………………………………………………………... 38
Figure 8 Tumor-to-muscle ratio comparison between 188Re-BMEDA and 188Re-liposome……... 39
Figure 9 The establishment of the orthotopic human NSCLC tumor-bearing mice……………… 40
Figure 10 No apparent nuclear medicine signal was detected by the nanoSPECT/CT in the thoracic cavity…………………………………………………………………………... 41
Figure 11 The accumulation of 188Re-liposome in the orthotopic tumor model…………………... 42
Figure 12 The overall bio-distribution of tumor-free or tumor-bearing mice underwent the injection of 188Re-liposome injection…………………………………………………… 43
Figure 13 The newly formed blood vessels was highlighted by CD31 immunohistochemistry staining………………………………………………………………………………….. 44
Figure 14 The pharmacokinetic analysis for the 188Re-BMEDA or 188Re-liposome was presented as radioactivity to time curve…………………………………………………………… 45
Figure 15 The therapeutic strategy for the use of 188Re-liposome in NSCLC-bearing mice treatment………………………………………………………………………………… 46
Figure 16 The therapeutic efficacy was assessed by BLI observation…………………………... 47
Figure 17 The quantified BLI signal for the investigation of tumor growth………………………. 48
Figure 18 The Kaplan-Meier survival curve…………………………………………………….. 49
Figure 19 The establishment of orthotopic human head and neck squamous cell cancer (HNSCC) by two different approaches…………………………………………………………….. 71
Figure 20 The 188Re-liposome distribution in the HNSCC tumor-bearing mice was determined by Cerenkov luminescent imaging (CLI) …………………………………………….. 72
Figure 21 The bio-distribution of orthotopic human HNSCC tumor-bearing mice……………….. 73
Figure 22 The pharmacokinetics in the human HNSCC tumor-bearing mice……………………... 74
Figure 23 The tumor suppressive effect was validated by the BLI investigation……………….. 75
Figure 24 The quantification of the HNSCC-bearing mice undergone either the treatment of 188Re-BMEDA or 188Re-liposome………………………………………………………. 76
Figure 25 The survival curve of 188Re-BMEDA and 188Re-liposome treated mice……………... 77
Figure 26 The immunohistochemistry sections were stained with Ki67 to perform as the growth index of tumor…………………………………………………………………………... 78
Figure 27 Gene set enrichment analysis (GSEA) analysis………………………………………… 79
Figure 28 The gene expression difference was concluded and listed by GSEA within hsa-let-7 gene set………………………………………………………………………………….. 80
Figure 29 The microarray results were analyzed by Ingenuity Pathway Analysis (IPA) ……….. 81
Figure 30 The mRNA levels of the microRNAs and potent oncogenes…………………………… 82

Contents of Tables



Table 1 Current liposomal drugs used in clinic………………………………………………... 6
Table 2 Bio-distribution analysis of 188Re-BMEDA radiopharmaceutical compound in subcutaneous human NSCLC NCI-H292 tumor-bearing mice……………………….. 30
Table 3 Bio-distribution analysis of PEGylated 188Re-liposome administration in subcutaneous human NSCLC NCI-H292 tumor-bearing mice …………………….. 31
Table 4 Pharmacokinetic parameters of 188Re-BMEDA and 188Re-liposome in nude mice…… 32
Table 5 Tumor-to-non-tumor absorbed radiation dose ratio…………………………………… 32
Table 6 The Kaplan-Meier parameters evaluated by log-rank test…………………………….. 32
Table 7 Bio-distribution analysis of 188Re-BMEDA radiopharmaceutical compound in orthotopic human HNSCC FaDu tumor-bearing mice………………………………... 67
Table 8 Bio-distribution analysis of 188Re-liposome radiopharmaceutical compound in orthotopic human HNSCC FaDu tumor-bearing mice…………………….. ………… 68
Table 9 The pharmacokinetic parameters in human head and neck squamous cell carcinoma FaDu orthotopic tumor-bearing mice……………………………………………….. 69
Table 10 Gene set enrichment analysis concluded the ranking of highly regulated microRNA gene sets……………………………………………………………………………….. 70


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