臺灣博碩士論文加值系統

在此研究中，將鎝99m標誌於所合成出來的配位子2,2,4,9,9-pentamethyl-4,7-diaza-1,10-decanedithiol及2,2,9,9-Tetramethyl- 4,7 -diaza-1,10-decanedithiol (PDD和TDD)，進而溶於Lipiodol中，透過肝動脈注射來探討帶肝腫瘤之大白鼠之生物分佈。
PDD和TDD兩種螯合劑之合成步驟分別是5個步驟和4個步驟，實驗條件均逐一確立完成。而其結構是利用NMR光譜、IR光譜與EA元素分析予以鑑定確認。
鎝99m之標誌主要利用不同pH 值的緩衝溶液，以酒石酸亞錫(Stannous tartrate)還原過鎝酸根離子(99mTcO4-)，形成鎝氧核離子99mTcO3+再與PDD和TDD兩種螯合劑結合而得。放射化學特性的鑑定係利用電泳動分析法、溶劑萃取法及薄層分析法，以探討鎝99m─PDD和鎝99m─TDD之標誌效率、親脂性大小、電性及穩定性。由所得結果發現，此兩種鎝99m 錯合物(99mTc-PDD 和 99mTc-TDD)均有很高的標誌效率(~85% and ~82%)，呈現中性，以及親脂性，穩定度甚佳。將前製標誌好鎝99m之錯合物以二比一的比例(V/V)加於lipiodol中，再以生理食鹽水清洗之，取其lipiodol層，即99mTc-PDD-Lipiodol 和99mTc-TDD-Lipiodol。
取24隻種有肝腫瘤之公鼠自肝動脈各施打0.2mCi的99mTc-PDD-Lipiodol 和 99mTc-TDD-Lipiodol。另外以同樣數目的老鼠自老鼠尾巴靜脈各施打0.3mCi的99mTc-PDD和 99mTc-TDD之生理食鹽水溶液。上述老鼠經注射99mTc-錯合物後經四個時間間隔，分別為10分鐘、1小時、3小時及24小時，分別將老鼠犧牲並取其重要器官及組織，測各器官與組織的放射活性。由以上生物分佈實驗結果，顯示肝腫瘤的部分有很高的放射活性；另一方面，正常的肝組織也有很高的吸收，但是仍然比肝腫瘤的部分低了許多。而在肺臟的部分， 99mTc-PDD-Lipiodol和 99mTc-TDD-Lipiodol在施打後1小時，有很高的吸收量，但是會隨著時間的增加而有快速下降的趨勢。

In this study, 99mTc complexes with 2,2,4,9,9-pentamethyl-4,7- diaza-1,10-decanedithiol (PDD) and 2,2,9,9-Tetramethyl-4,7-diaza-1,10- decanedithiol (TDD) mixed and dissolved in lipiodol were administrated in hepatoma-bearing rats by intrahepatic arterial injection. Biodistribution in the rats as well as hepatoma uptake of 99mTc-PDD and 99mTc-TDD in lipiodol have been explored.
The synthesis of the chelating agent─PDD and TDD proceeded with 5 and 4 steps﹔optimal conditions either for PDD or for TDD were established. PDD and TDD were identified by NMR, IR and EA.
Labeling PDD and TDD with 99mTc were carried out by mixing 99mTcO4-/saline with the ligand solution of PDD or TDD, saturated stannous tartrate solution, and a specific pH buffer. The solution mixture was shaken for 20 min for accomplishing the 99mTc complexation . The labeling efficiency, lipophilicity and stability of 99mTc-PDD and 99mTc-TDD were determined by electrophoresis, solvent extraction and thin layer chromatography. For the results, 99mTc-PDD and 99mTc-TDD was characterized to be of high labeling yield (~85% and ~82%), neutrality, high lipophilicity, and high stability. The complexes were mixed with lipiodol at the ratio of two to one (V/V), and then washed by saline. The lipiodol layer was separated as the 99mTc-complex solutions in lipiodol, 99mTc-PDD-lipiodol and 99mTc-TDD-lipiodol.
Twenty four male rats bearing with hepatoma were injected with approximately 0.2 mCi of either 99mTc-PDD-lipiodol or 99mTc-TDD-lipiodol via the hepatic artery. The same number of male rats bearing with hepatoma were injected with approximately 0.3 mCi of either 99mTc-PDD or 99mTc-TDD via the tail veins. The rats were separately sacrificed at 10 min, 1h, 3h and 24h postinjection. Various organs or tissues were dissected, weighed, and counted. Percent injected dose per gram of organ or tissue ( ％ID/g organ or tissue) was calculated from the radioactivitions measured. Uptake by hepatoma of either 99mTc-PDD or 99mTc-TDD was significant and about two-fold higher than the normal liver tissue. The uptake in the lung reached maximally high at 1h postinjection but then decreased rapidly either for 99mTc-PDD-Lipiodol or 99mTc-TDD-Lipiodol, which was initially injected via the hepatic artery.

目錄 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅰ
謝誌 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅲ
英文摘要 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅳ
中文摘要 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅵ
表目錄 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅷ
圖目錄 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． Ⅸ
第一章、前言 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 1
一、研究動機 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 1
二、研究目的 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 1
三、研究背景資料 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 2
四、研究內容概述 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 8
第二章、特性分析及原理 ．．．．．．．．．．．．．．．．．．．．．． 9
一、溶劑萃取法 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 9
二、電泳動分析法 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 10
三、薄層層析法 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 11
第三章、實驗部分 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 13
一、實驗藥品 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 13
二、實驗儀器 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 14
三、配位子的合成 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 16
四、99mTc標誌二胺二硫錯合物 ．．．．．．．．．．．．．．．．．．． 22
五、鎝99m標誌化合物之放化特性分析 ．．．．．．．．．．．．． 22
六、鎝99m標誌化合物之動物實驗 ．．．．．．．．．．．．．．．． 23
第四章、結果與討論 ．．．．．．．．．．．．．．．．．．．．．．．．． 26
一、官能基螯合劑─PDD和TDD─之合成與探討 ．．．．．． 26
二、PDD及TDD的化學特性探討 ．．．．．．．．．．．．．．．．．．． 27
三、PDD及TDD的生物特性探討 ．．．．．．．．．．．．．．．．．．． 32
第五章、未來展望 ．．．．．．．．．．．．．．．．．．．．．．．．．．．． 38
參考文獻 ．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．． 86

【1】 Wang S. J., Lin W. y.,Chen M. N., Shen L. H., Tsai Z. T., Ting G, Preparation and biodistribution of yttrium-90 lipiodol in rats following hepatic arterial injection, Eur J Nucl Med (1995), 22, 233-236
【2】 Wang S. J., Lin W. y.,Chen M. N., Hsieh B. T., Shen L. H., Tsai Z. T., Ting G. and Knapp F. F. Jr, Radiolabeling of lipiodol with generator-produced 188Re for hepatic tumor therapy, Appl Radiat Isot (1996), 47, 267-271
【3】 Wang S. J., Lin W. y.,Chen M. N., Hsieh B. T., Shen L. H., Tsai Z. T., Ting G. and Knapp F. F. Jr, Biodistribution of rhenium-188 lipiodol infused via the hepatic artery of rats with hepatic tumors, Eur J Nucl Med (1996), 23, 13-17
【4】 Jae Min Jeong a,d, *, Young Joo Kim a , Yoon Sang Lee a , Jun Il Ko b , Miwon Son b ,Dong Soo Lee a , June-Key Chung a,d , Jae Hyung Park c , Myung Chul Lee , Lipiodol solution of a lipophilic agent 188Re-TDD, for the treatment of liver cancer, Nucl Med and Biology 28 (2001) 197—204
【5】 Kowalsky RJ and Perry JR, Radiopharmaceuticals in Nuclear Medicine Appleton ＆ Lange, East Norwalk, USA (1987)
【6】 Hevesy G, Paneth F, Die loslichkeitt des bleisulfides and bleichromates. Z anorg Chem 17 (1913) 379
【7】 Hevesy G, The adsorption and translocation of lead by plants. A contribution to the application of the method radioactive indicators in the investigation of the change of substance in plants Biochem J 17 (1923) 439
【8】 Hevesy G, Adventures in Radioisotope Research, Pergamon Press, NY, USA (1962)
【9】 Saha GB, Fundamental of Nuclear Pharmacy 3rd edition, Springer-Verlag, NY, USA (1992)
【10】 Stinson, A. E., and M. L. Calhoun. Digestive system. In Textbook of Veterinary histology. Dellmann, H. D., E. M. Brown(ed.), Lea＆Febiger, Philadelphia, (1976) 207-213
【11】 Maclachlan, N. J., and J. M. Cullen. Liver, Billary system, and Exocrine Pancrease. In Thomson’s Special Veterinary Pathology, 2nd.ed., William, W.C. M. D. Mcgavin(ed.), Mosboy Chicago Chicago, USA, (1995) 81-115
【12】 Millward, G. H., and A.M. Jezequel. 1985. Normal histology and structure in liver and biliary disease. 2nd ed., Edited by R. Wright, G. H. Millward-Sadler, K.G.M.M. Alberti and S. karran. W. B. Sounder, Philadelphia, (1985) 13-44
【13】Bergman, J. R. Nodular hyperplasia in the liver of the dog: An association with changes in the Ito cell population. Vet. Pathol. 22 (1985) 427-443
【14】Chervu LR, Nunn AD and Loberg MD, Radiopharmaceuticals for heptobiliary imaging. Semin Nucl Med XΠ (1982) 5-17
【15】Nakakuma K, et al. Hepatocellular carcinoma and metastatic cancer detected by iodized oil. Radiology 154 (1985) 15-17
【16】Yomoto Y, et al. Hepatocellular carcinoma detected by iodized oil. Radiology 154 (1985) 19-24
【17】Nakakuma K, et al. Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer. Cancer 52 (1983) 2193-2200
【18】Ohishi H, et al. Hepatocellular carcinoma detected by iodized oil:
use of anticancer agents. Radiology 154 (1985) 25-29
【19】Madsen MT, et al. Dosimetry of iodine-131 Ethiodol in the treatment of hepatoma. J Nucl Med 29 (1988) 1033-1044