臺灣博碩士論文加值系統

惡性腫瘤由於細胞分裂增殖過速，血管之增生趕不上細胞成長速率，因此較大之腫瘤其內部常因血液及氧氣供應不足而有相當比例之缺氧或壞死細胞。缺氧細胞對於游離輻射之耐受性約為正常細胞的3倍，對於腫瘤之放射治療，如何判定其缺氧部位並予以適當之增敏處理，以提高游離輻射對缺氧細胞之殺傷力，乃為治療能否成功之重要因素。另外，在心肌梗塞或中風時，亦可見組織局部缺氧現象，若能及早測知並進行治療，常可避免器官功能之惡化或甚至恢復功能。
Misonidazole之代謝產物可選擇性地積聚於缺氧細胞，以氟-18同位素標記之18F-FMISO配合正電子電腦斷層掃瞄 (positron emission tomography, PET) 設施，已在台北榮總國家正子/迴旋加速器中心(National PET/Cyclotron Center, NPCC)成功地應用於體內腫瘤診斷及因急性心肌梗塞或中風所引起之局部器官或組織缺氧狀況之診斷。然而F-18是正子放射核種，只能在有PET與Cyclotron設備的醫學中心才能進行；若使用加馬放射核種 (如鎝-99m) 標記核醫藥物，雖然在定量分析上不如PET，但幾乎所有大型醫院均可進行單光子放射電腦斷層掃瞄(SPECT)，故以99mTc標記之缺氧組織造影核醫藥物目前仍在廣泛研究中。
本研究使用核能研究所合成之N4配位子HL91，進行鎝-99m標幟配方研究製備鎝-99m金屬錯合物(99mTc-HL91)，再進行其分配係數（partition coefficient，可視為脂溶性指標）測定、安定劑配方研究以及缺氧細胞攝取實驗，並與[18F]FMISO（現已被公認為缺氧組織造影診斷之golden standard）相比較。研究結果將可驗證此99mTc-HL91錯合物的化學及生物特性，以評估此核醫藥物之有效性，作為進一步之臨床應用參考。

In tumors, because of the rapid, disorganized mode of growth, tumor cells proliferate more rapidly than the vasculature. A larger solid tumor usually contains necrotic centers resulted from the vascular inadequacy as well as several layers of hypoxic cells adjacent to the necrosis cells. The hypoxic cells are more resistant to low LET ionization radiation by a factor of nearly three compared with normoxic cells. To increase the sensitivity of the hypoxic cells to ionization radiation is a common problem in tumor radiation therapy. In the heart tissue, hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. In patients with stroke, hypoxia has been associated with the penumbral region, where an intervention could preserve function.
The reduction product of misonidazole incorporates into hypoxic cells specifically. The 18F-labeled misonidazole has been successively used in NPCC in clinical study with PET for hypoxia diagnosis in tumor, myocardium and brain. The PET image of 18F-FMISO, when compared with that of 18F-FDG, can be used to determine the ratio of hypoxic to aerobic fractions in tumor, which is very critical in clinical tumor treatment. Since SPECT is more widespread than PET in Taiwan, though not as good as PET in quantitative study, the 99mTc-labeled hypoxia-imaging agent for SPECT is still the “hot spot” in domestic nuclear medicine research.
In this study, the formulation of HL91 cold kits was investigated to optimize the complex formation of 99mTc-HL91. The partition coefficient (an index for lipophilicity) of 99mTc-HL91 was determined and the stability of 99mTc-HL91 complex was studied. The uptake ratio of 99mTc-HL91 complex and 18F-FMISO toward normoxic and hypoxic cells were examined. The SPECT imaging of sarcoma-bearing mice with 99mTc-HL91 was performed and compared with 18F-FMISO PET imaging which was considered the golden standard for hypoxia detection. From the experimental results, the chemical and biological properties and also the potential of the complex 99mTc-HL91 as hypoxia SPECT imaging agent were characterized.

壹、中文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧2
貳、英文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧4
參、前言‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧6
肆、材料、儀器與方法
一、材料與儀器‧‧‧‧‧‧‧‧‧‧‧‧13
二、實驗方法
1.99mTc-HL91之最佳化製備‧‧‧‧‧16
2.99mTc-HL91脂溶性與亞錫含量測定‧19
3.缺氧及富氧細胞之攝入率測定‧‧‧23
4.生物體分佈試驗‧‧‧‧‧‧‧‧‧26
5.MIRD評估‧‧‧‧‧‧‧‧‧‧‧‧29
伍、結果與討論‧‧‧‧‧‧‧‧‧‧‧‧30
陸、結論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧64
柒、參考文獻‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧68

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