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研究生:張瑋庭
研究生(外文):Wei-Ting Chang
論文名稱:放射性氟標幟核苷類似物用於藥物治療前腫瘤篩選及治療期間腫瘤療效評估之研究
論文名稱(外文):The study of radiofluorinated nucleoside analogues for screening tumor type before Clolar treatment and evaluating tumor treatment response during treatment course
指導教授:王信二
指導教授(外文):Hsin-Ell Wang
學位類別:碩士
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暨研究所
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:2009
畢業學年度:97
語文別:英文
論文頁數:54
中文關鍵詞:核苷類似物FMAUclofarabine微正子斷層造影血癌治療
外文關鍵詞:Nucleoside analoguesFMAUclofarabinemicroPETleukimia treatment
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目的:如何在腫瘤治療期間正確且儘快地評估療效,常為腫瘤治療能否成功的關鍵。傳統電腦斷層(computed tomography)及磁振造影(magnetic resonance imaging)所得解剖性影像僅能偵測腫瘤體積,並不能確實反映腫瘤療效。放射性同位素標記之核��類似物結合正子斷層造影,可用於即時監測腫瘤細胞增生速率。本實驗室過去研究指出,18F-FMAU於腫瘤的積聚程度與腫瘤的增生速率成正比。本研究使用荷NG4TL4之FVB/n小鼠,先將liposome載體標記111In以評估liposome服用後不同時間點於腫瘤與全身器官組織的積聚濃度,建立最佳治療計畫;之後將動物施以Lipo-VNB治療,分別以18F-FMAU做為核�ㄠ敦w,以非侵入性核醫分子造影監測腫瘤細胞增生速率,並與18F-FAc與18F-FDG 於同一動物腫瘤模式之結果比較,以評估18F-FMAU做為腫瘤療效評估造影劑之潛力。
方法:以自行合成之2-O-(trifluoromethylsulfonyl)-1,3,5-tri-O-benzoyl- ��-D-ribofuranose做為標記前驅物,約經3.5小時可得18F-FMAU產物,放射化學純度>98%,放射化學產率經衰減校正可達15~20%。荷有NG4TL4肉瘤之小鼠,於排定時間由尾靜脈給予三次化療藥物 (6 % Pegylated VNB-liposome)治療。並於腫瘤誘發後第8、11、15及18天,由尾靜脈注射放射性造影劑(18F-FMAU、18F-FDG及18F-FAc)進行微正子造影以及18F-FMAU生物分布試驗以評估腫瘤治療療效。VNB藥物對於NG4TL4細胞之抑制作用由流式細胞儀分析。
結果:於荷腫瘤小鼠之18F-FMAU生物分布實驗中指出,腫瘤/肌肉攝取比值於治療前後有明顯的下降,從2.13 �b 0.39 (腫瘤誘發後第8天) 經3次治療後,降至1.07 ± 0.37(腫瘤誘發後第18天)。分析18F-FMAU微正子造影影像結果得知,治療組的腫瘤/肌肉比由2.33 ± 0.16 (腫瘤誘發後第8天),經3次治療後,降至1.23 ± 0.07 (腫瘤誘發後第18天),控制組者比值則維持穩定(腫瘤誘發後第8天為2.33 ± 0.16, 腫瘤誘發後第18天為2.30 ± 0.22)。但使用18F-FDG PET與18F-FAc PET造影者治療前後的腫瘤/肌肉比值均無明顯改變。微正子造影結果亦由生物分布實驗得到證實。於細胞分布實驗中證實,於VNB藥物培養48小時後,細胞增生速率受到抑制。
結論:由評估腫瘤反應研究中顯示與腫瘤細胞增生速率相關之正子造影劑18F-FMAU,可做為腫瘤療效評估使用。

關鍵字:核��類似物、微正子斷層造影、FMAU

目的:Clofarabine (2-chloro-2’-fluoro-2’-deoxy-9-��-D-arabinofuranosyl- adenine)為新一代的腫瘤治療藥物。近年來研究指出,clofarabine對多種實質腫瘤及血液方面疾病有治療效果。若能利用追蹤劑原理(tracer principle),將clofrabine以放射性同位素標誌,輔以核子醫學影像系統,即可做為預知療效之工具。本研究建立18F-clofrabine之合成方法並評估其做為clofrabine治療前腫瘤篩選指標之可行性,以避免不必要毒性與花費。
方法:以自行合成之2-O-(trifluoromethylsulfonyl)-1,3,5-tri-O-benzoyl- ��-D-ribofuranose做為標記前驅物,約經3.5小時合成可得18F-clofarabine產物,放射化學純度>98%,放射化學產率經衰減校正皆可達10~15%。進行18F-clofarabine在A549 (肺表皮腺癌)、GBM (多形性神經膠母細胞瘤)、H1299 (非小細胞肺癌)、HL60 (急性前骨髓性白血病)及HT 29 (大腸直腸腺瘤)細胞的攝取實驗。於NOD-SCID小鼠右腿種植A549、GBM、H1299或HT 29腫瘤細胞,待腫瘤成長至約100~150 mm3時,進行18F-clofarabine之生物分布實驗及microPET造影。
結果:細胞攝取實驗顯示五種細胞對18F-clofarabine之藥物攝取比值(cell-to-medium ratio)在加入藥物培養後皆快速達到平衡狀態。其中HL60細胞之攝取比值最高,培養兩小時可達131.50 ± 5.62。在生物分布實驗中,於荷腫瘤小鼠尾靜脈注射18F-clofarabine。兩小時後,HT29 腫瘤對肌肉攝取比值為四種動物模式中最高達2.84 ± 0.47。微正子造影結果亦與生物分布實驗結果相符。由實驗結果可知,不同細胞對於18F-clofarabine有不同的攝取,而積聚量是否與療效相關則待進一步實驗證實。
Conclusion:由細胞攝取實驗、生物分布實驗及影像結果顯示,18F-clofarabine可用於PET造影,提供惡性病灶的偵測以及非侵略性的療效反應評估,篩選適合使用此藥物治療的病人。

關鍵字:腺嘌呤類似物、微正子斷層造影、血癌治療、clofarabine
Objective: The key point of successful tumor treatment is to get the accurate information of tumor cell proliferation and evaluate the therapeutic efficacy during the treatment course. Computed tomography (CT) or magnetic resonance imaging (MRI) modalities can only detect the tumor size not the tumor response. Radio-labeled nucleoside analogues as a positron emission tomography (PET) probe could provide the information of therapeutic efficacy. In this study, liposome will be labeled with In-111 to give the radioactive surrogate. The biodistribution of 111In-Liposome will be investigated in NG4TL4 tumor-bearing mice model to establish the optimal treatment protocol. We will evaluate the potential of 18F-FMAU-PET as a therapeutic efficacy index after Lipo-VNB treatment and compare with those of 18F-FDG- and 18F-FAc-PET.
Method: Starting from benzoate-protected arabinose triflate, 18F-FMAU and 18F-clofarabine was prepared in 3.5 h via a two-step synthesis with high radiochemical purity (>98%) and acceptable radiochemical yield (15-20%, decay corrected). In tumor treatment response study, the 6% Pegylated VNB-liposome drug delivery, 18F-FMAU biodistribution study, and micro-PET imaging studies with 18F-FMAU, 18F-FDG and 18F-FMAU were conducted in the NG4TL4 tumor-bearing mice at designate time according to the study protocol. The VNB cytotoxity was measured through flow cytometry assays.
Result:The result of biodistribution studies of 18F-FMAU showed the significant reduction in T/M ratio after three-dose treatment, 2.13 �b 0.39 (day 8) to 1.07 ± 0.37(day 18). Regional radioactivity concentrations of the ROIs drawn around the tumor and muscle on images were derived from 18F-FMAU PET (obtained 1 h pos-tinjection). After three-dose treatment, the tumor-to-muscle ratio (T/M) of treated group dropped from 2.33 ± 0.16 to 1.23 ± 0.07, while that of control group remained steady (2.33 ± 0.16 to 2.30 ± 0.22). In 18F-FDG PET and18F-FAc PET groups, there is no statistical difference in T/M ratio between the therapeutic and control group. The results of microPET imaging were consistent with those of biodistribution studies. And flow cytometry assays verified the proliferative rate inhibition at 48h after VNB drug incubation.
Conclusion: The tumor treatment response study demonstrated that the proliferating rate related probe, 18F-FMAU, was a proper PET probe for monitoring the cytotoxicity and therapeutic efficacy of pegylated VNB-liposome in a tumor-bearing animal model.

Key words: Nucleoside analogues, microPET, FMAU

Objective:Clofarabine (2-chloro-2’-fluoro-2’-deoxy-9-��-D- arabinofuranosyl adenine) was the focus of development and is now a next-generation tumor treatment drug developed for the treatment of solid and hematologic tumors. The ability to image the distribution of clofarabine noninvasively throughout the body could be of great value in the diagnosis, staging and treatment of malignancies. In this study, we will establish the preparation of 18F-clofarabine and assess its feasibility as an early index before clofarabine treatment to avoid unnecessary cytotoxicity and expenses.
Materials and Methods:Starting from benzoate-protected arabinose triflate, 18F-clofarabine was prepared in 3.5 h via a two-step synthesis with high radiochemical purity (≧98%) and acceptable radiochemical yield (10-15%, decay corrected). The cellular uptake of 18F-clofarabine in A549 (Lung epidermar adenocarcinoma) cell, GBM (Human glioblastoma multiforme) cell, H1299 (Non-small cell lung carcinoma) cell, HL60 (Human acute promyelocytic leukemia) cell and HT-29 (Human colorectal adenocarcinoma) cell lines was assayed. NOD-SCID mice were inoculated with A549, GBM, H1299 and HT29tumor cells in the right flank to grow tumor. The biodistribution study and micro-PET imaging of tumor-bearing mice were performed after 2 h intravenous administration of 18F-clofarabine.
Results and Discussion:Rapid cellular uptake of 18F-clofarabine in the five cell lines were observed at the first 30 min, then increased slowly till 2 h incubation. Among these, HL60 cells exhibited the highest cell to medium (C/M) ratio during 2 h incubation (131.50 ± 5.62). The results of biodistribution of 18F-clofarabine in the tumor bearing mice, the tumor to muscle ratio of HT29 tumor (2.84 ± 0.47) was the highest in the four tumor-bearing mouse models. MicroPET imaging of 18F-clofarabine were consistent with those observed in biodistribution studies. HT29 tumor can be clearly delineated at 2 h post i.v. injection of clofarabine. The preliminary study of 18F-clofarabine indicated that the accumulation of clofarabine was tumor-dependent.
Conclusion: The results obtained in cellular uptake, biodistribution and microPET imaging studies demonstrates the value of 18F-clofarabine as a potent PET probe to select the suitable patients for the tumor treatment using clofarabine.

Key words: Adenosine analogues, microPET, leukemia treatment, clofrabine
PART I CONTENT
Chinese abstract 1
English abstract 3
Introduction 5
Materials and methods 9
1. Materials 9
2. Radio-synthesis of 18F-FMAU 9
3. Radiosynthesis of 18F-Fluroacetate (18F-FAc) 12
4. Radio-synthesis of 18F-FDG 13
5. Cell cultures 13
6. Tumor xenografts in mice………………………………………………... 13
7. Treatment response study protocol………………………………………. 13
8. Tissue sampling and radioactivity measurements…………………………………………14
9. MicroPET imaging study…………………………………………………………………..14
10. Cell cycle analysis………………………………………………………………………….15
11. Statistical analysis………………………………………………………............................15
Results 16
1. Radiosynthesis of 18F-FMAU and 18F-FAc …………… 16
2. Therapeutic efficacy of treatment response study……………………….. 17
3. Biodistribution study…………………………………………………… 18
4. MicroPET imaging………………………………………………………. 20
5. Flow cytometric analysis…………………………………………… 24
Discussion 25
Conclusion 29
Reference 30

PART II CONTENT
Chinese abstract 33
English abstract 35
Introduction 37
Materials and methods 40
1. Materials 40
2. Radio-synthesis of 18F-clofarabine 41
3. Cell cultures 42
4. In-vitro accumulation of 18F-clofarabine 42
5. Tumor xenografts in mice 43
6. Tissue sampling and radioactivity measurements 43
7. MicroPET imaging study …43
8. Statistical analysis 44
Results 45
1. Radio-synthesis of 18F-clofarabine 45
2. In-vitro accumulation of 18F-clofarabine 45
3. Biodistribution of 18F-clofarabine 47
4. MicroPET imaging of 18F-clofarabine 48
Discussion 49
Conclusion 51
Reference 52
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