中文摘要
癌症至今仍是人類最主要的死因，據估計全球每四人中就有一人是死於癌症。因此，癌症的早期診斷與治療便成為現今癌症研究的主要課題。利用放射性藥物的核子診斷醫學，於腫瘤偵測亦或在腫瘤治療的應用上，扮演相當重要的角色。本篇論文，主要是利用三羰基鎝99m(I)標誌方法將放射性核種-鎝99m直接標誌於三種不同的生物分子上，包括標誌單株抗體抗癌藥物賀癌平(Herceptin)、耦合組胺酸的體抑素衍生物(histidine-tagged octreotide derivatives)及蛋白質基底的人類血清白蛋白奈米粒子(protein-based HSA nanoparticles)。分別對其三羰基鎝99m(I)標誌產物進行放射化學特性的研究，評估其作為單光子發射斷層造影劑的可能性。論文主要包含三個研究主題：研究一，評估三羰基鎝99m(I)直接標誌單株抗體抗癌藥物賀癌平的可行性。研究二，評估三羰基鎝99m(I)直接標誌耦合組胺酸的體抑素衍生物的可行性，並將其標誌產物打入接種胰臟癌腫瘤的小鼠體內進行活體試驗的評估。研究三，製備三羰基鎝99m(I)標誌人類血清白蛋白奈米粒子作為單光子發射斷層造影劑。
由研究一結果得知，透過直接標誌法可於溫和的反應條件下得到三羰基鎝99m(I)標誌的賀癌平產物，且此標誌產物仍保有其對於人類上皮生長因子第二接受器(Human Epidermal Growth Factor Receptor 2，HER-2)的生物親和性。於體外血清穩定度試驗中，更表現出良好的血清穩定度。此結果對於未來進行動物實驗的評估測試相當有利。由研究二結果得知，耦合組胺酸的體抑素衍生物可以固相胜肽合成法成功製備得到，且具有對於2a型體抑素接受器(Somatostatin sst2a Receptor)的生物親和性。透過直接標誌法亦可於溫和的反應條件下得到三羰基鎝99m(I)標誌的耦合組胺酸的體抑素衍生物產物。而從生物分佈及造影實驗中得知，其中的三羰基鎝99m(I)標誌的耦合3個組胺酸的體抑素衍生物及三羰基鎝99m(I)標誌的耦合5個組胺酸的體抑素衍生物，兩者分別於給藥後四小時或八小時腫瘤累積吸收達到最高值，且可以觀察到明顯的腫瘤輪廓影像。由此可知，三羰基鎝99m(I)標誌的耦合組胺酸的體抑素衍生物有其潛能作為腫瘤造影劑，特別是應用於偵測表現有體抑素接受器的腫瘤。由研究三結果得知，人類血清白蛋白奈米粒子可由去溶劑法製備得到，透過直接標誌法亦可於溫和的反應條件下得到三羰基鎝99m(I)標誌的人類血清白蛋白奈米粒子。未來亦可利用人類血清白蛋白奈米粒子作為載體，包覆攜載化療藥物作為治療之用途，使三羰基鎝99m(I)標誌的人類血清白蛋白奈米粒子成為同時具有診斷與治療雙功能的診療劑。

Abstract
At present, cancer remains the major cause of human death in the world, accounting for nearly 1 of every 4 deaths. The current focus of modern cancer researches is on cancer early detection and advanced treatments. Diagnostic nuclear imaging using radiopharmaceuticals is playing an increasingly important role in the tumor detection as well as therapeutic applications. In this dissertation, the 99mTc-tricarbonyl-based radiolabeling method was attempted for direct labeling of 99mTc to three different biomacromolecules, including: Herceptin (trastuzumab), histidine-tagged octreotide derivatives and protein-based HSA nanoparticles. The radiochemical properties of the resultant 99mTc-labeled biomacromolecules were characterized and investigated for their potentials on SPECT imaging. Thus, three research projects are included in this dissertation: (I) Direct 99mTc labeling of Herceptin (trastuzumab) by 99mTc(I)-tricarbonyl ion, (II) 99mTc(I) Radiolabeling of histidine-conjugated octreotide derivatives and preliminary in vivo evaluation in AR42J tumor-bearing mice, (III) The novel preparation of 99mTc(I)-labeled human serum albumin (HSA) nanoparticles as a SPECT imaging agent.
The first study shows that 99mTc(I)-trastuzumab was prepared by simple incubating Herceptin (trastuzumab) with [99mTc(OH2)3(CO)3]+ in normal saline under mild radiolabeling condition. The tumor-targeting capability of the 99mTc(I)-labeled trastuzumab was validated with high binding affinity to HER-2-overexpressing cancer cells. Well in vitro stability of 99mTc(I)-trastuzumab in serum suggests its potential as a SPECT imaging agent in vivo. The second study shows that octreotide together with its three histidine-tagged octreotide derivatives (his-octreotide, his3-octreotide and his5-octreotide) were successfully synthesized using a facile solid phase peptide synthesis method. This study also shows that all the histidine-tagged octreotide derivatives demonstrated similar high binding affinities as octreotide to the human somatostatin sst2a receptor. [99mTc(OH2)3(CO)3]+ was also applied as an efficient reagent for direct labeling histidine-conjugated octreotide derivatives by a simple mixing procedure under mild condition. Biodistribution and imaging studies of the 99mTc(I)-his3-octreotide and 99mTc(I)-his5-octreotide demonstrated the highest tumor uptake at 4 h and 8 h postinjection, respectively, and both displayed a clear tumor delineation. It is anticipated that the 99mTc(I)-labeled histidine-conjugated octreotide derivatives will be useful for imaging SSTRs-positive tumors. The third study established a new and efficient protocol to prepare 99mTc(I)-HSA-NPs conjugates with high purity and stability. Labeling of 99mTc(I) to HSA-NPs was also performed in the similar mild way as aforementioned, and achieved high radiochemical yield and specific activity. In the future, the HSA-NPs could be further loaded with anticancer drugs for potential therapeutic uses. The versatility and attractive properties suggest that 99mTc(I)-HSA-NPs have great potentials for future theranostic applications.

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