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系統識別號 U0026-1311201217095600
論文名稱(中文) 開發蛋白質脢專一之前驅探針與前驅藥物以便即時腫瘤造影與治療
論文名稱(英文) Real-time cancer imaging and therapy via protease specific pro-probe and pro-drug activation
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 101
研究生(中文) 莊智弘
研究生(英文) Chih-Hung Chuang
學號 s58941400
學位類別 博士
語文別 英文
論文頁數 122頁
口試委員 指導教授-王育民
召集委員-黃暉升
口試委員-吳昭良
口試委員-鄭添祿
口試委員-黃奇英
口試委員-王雲銘
中文關鍵字 蛋白質脢  腫瘤造影  腫瘤治療 
英文關鍵字 protease  tumor imaging  tumor therapy 
學科別分類
中文摘要 蛋白酶在許多疾病中都扮演十分重要的角色,在許多惡性腫瘤中蛋白質酶都被報告與腫瘤的生長、血管新生、侵犯與轉移均占有很重要角色,例如:攝護腺特異抗原蛋白酶(PSA)或第二型基質金屬蛋白酶(MMP2),因此追蹤體內蛋白酶的活性與開發具蛋白酶專一活化特性之前驅蛋白藥物,以便對病人進行量身定作之個人化醫療相當重要,針對此目的我們有如下的三個目的,(1):我們針對蛋白酶設計開發出具蛋白酶專一性之前驅探針,此探針包含一造影探針基團18F-Tetramethylrhodamine (18F-TMR) 與一親水性之胜肽-聚乙二醇基團 (peptide-PEG)兩部分,當蛋白酶專一性切除親水性胜肽-聚乙二醇基團後,疏水性之造影探針即會沉澱而累積產生訊號,經由造影便可評估蛋白質酶於不同組織或病症的表現。進而對蛋白酶表現之疾病進行量身定作之醫療與評估。(2):我們也針對細胞內的蛋白酶來設計專一性之前驅探針,此探針包含一造影探針基團(I131-FITC) 與一可自由穿透細胞膜的穿膜胜肽,此照影探針可自由進出細胞,當胞內的蛋白酶專一性切除穿膜胜肽,造影探針即會沉澱而累積產生訊號,經由造影便可評估蛋白質酶於不同組織或病症的表現。(3):為了開發具有臨床應用價值的蛋白質酶前驅藥物,我們利用蛋白質酶專一的受質胜肽來連結兩個不同功能的蛋白質。其中一個為具有膜穿孔能力的人類Perforin;另一端連結上具有誘發細胞凋亡能力的Granzyme B或是CEBPD。當蛋白酶專一性切除受質胜肽會釋放出具有膜穿孔能力的Perforin與具有誘發細胞凋亡能力的Granzyme B或是CEBPD,進而毒殺腫瘤細胞。我們的結果顯示18F-TMR可專一地累積於MMP2表現細胞HT1080,而非對照組的MCF7細胞。並且於小鼠腫瘤動物模式中發現,正子造影與螢光影像的結果都顯示,18F-TMR的訊號會大量累積於MMP2表現的HT1080腫瘤,而非對照組的MCF7腫瘤,證明此造影探針可以於活體內追蹤蛋白酶的活性。另外,我們所開發針對HCV NS3-4A蛋白酶活性的照影探針,也可以專一的累積於NS3-4A Huh7細胞中,而非對照組的Huh7細胞。並且於小鼠腫瘤動物模式中發現,單光子造影的結果都顯示,照影探針的訊號會大量累積於NS3-4A Huh7細胞中,而非對照組的Huh7細胞,證明此造影探針可以於活體內追蹤細胞內蛋白酶的活性。最後,我們的實驗顯示,我們發現具攝護腺特異抗原(PSA)專一活化特性的穿孔素PSA-乙型顆粒溶解酶,可以選擇性的殺死表現攝護腺特異抗原的LNCaP 細胞,而不會殺死對照組PC3 細胞,相似成果亦顯現於穿孔素PSA-乙型顆粒溶解酶選擇性的殺死第二型基質金屬蛋白酶表現的PC3細胞。並且可以藉由活化細胞內caspase8與caspase3的活性來造成細胞凋亡,並且發現同時給予前驅藥物 Perf-CEBPD與Perf-GB的治療比單獨給予更具有效。根據以上的成果,我們相信此策略將可提供一新穎的腫瘤造影與治療方法,以利即時的腫瘤造影與療效評估。此策略的成功將非常便利未來針對蛋白酶相關疾病的診斷、治療選擇與療效評估,以達成最佳化之個人化醫療。
英文摘要 Tumors are characterized by overexpression of various proteases including prostate specific antigen (PSA) and matrix metalloproteinases (MMPs). Proteases have been an attractive targeted enzyme for development of both imaging and therapy agent for cancer. Therefore, we aim to develop the protease specific protein-drug delivery systems for cancer therapy and to develop the clinical device applicable protease specific imaging pro-probe for cancer detection. First, we generated a protease-substrate probe to allow in vitro and in vivo detection of the protease activity by micro-positron emission topography (micro-PET). These probes consist a hydrophobic tetramethylrhodamine-Lys -18F (TMR-18F) motif and a hydrophilic protease substrate sequence (GPLGV), linked to PEG5000 to form TMR-18F-peptide-PEG probe (TMR-18F-peptide). Upon protease cleavage of TMR-18F-peptide, hydrophobic TMR-18F would preferential retain at sites displaying the protease activity. The radiation from TMR-18F is then detected by micro-PET to diagnose protease activity. Second, we also generated the HCV protease imaging probe for imaging the intra-cellular NS3-4A protease activity. The development of the HCV protease imaging probe based on the concept of “cell-penetrating conversion” via protease cleavage. upon the protease cleavage, the cell-penetrating peptide were removed and the image domain (FITC and I131 isotope) preferentially retains in the protease expressing cell and can enhance the sensitivity of detection. Third, we constructed the perforin base protease specific protein-drug delivery systems in which perforin and changeable drugs are linked by substrate peptides for PSA or MMP-2. The perforin and changeable drugs are activated upon cleavage of the linker peptides by PSA or MMP-2 at tumor sites. The activated changeable drugs (likes CCAAT-enhancer-binding proteins-δ or Granzyme B) can enter the cell, through the pore formed by the activated perforin, to induce apoptosis. Our results demonstrated the TMR-peptide-PEG probe can be specifically cleaved to produce TMR-lys (mw 948 Da) by purified MMP2 and MMP2-expressing HT1080 cell but not control MCF-7 cell. The MMP2-expressing cells or tumors selectively accumulated our probe at site of protease activity by optical imaging and PET imaging. The biodistribution and serum half-live results show TMR-18F-Peptides exhibited a rapid clearance in radioactivity over time in blood and most organs. Moreover, the probe signals were high in the MMP2-expressing tumor and low background in control tissues. The TMR-peptide-PEG probe can be specifically cleaved to produce TMR-lys (mw 948 Da) by purified MMP2 and MMP2-expressing HT1080 cell but not control MCF-7 cell. The MMP2-expressing cells or tumors selectively accumulated the hydrolyzed, hydrophobic TMR-lys at site of protease activity as revealed by optical imaging. Importantly, the TMR-18F-peptide-PEG probe was also preferentially converted to hydrophobic the TMR-18F on MMP2-expressing tumors. The biodistribution and serum half-live results show TMR-18F-Peptides exhibited a rapid clearance in radioactivity over time in blood and most organs. Moreover, TMR-18F-Peptides signals were high in the MMP2-expressing tumor and low background in control tissues. In additional, our result demonstrated the HCV protease imaging probe could accumulated into protease expressed NS3-4A Huh7 cell, but not control cells. Importantly, selective retention of image signal at the area of protease-expressing tumors in living animal by micro-SPECT imaging systems allowed us to detect the protease activity in living animal. Finally, our results of protease specific pro-drug indicate that stable pro-proteins (PerfPSACEBPD, PerfPSAGB, PerfMMP2GB and PerfMMP2CEBPD) expressing cells were generated and were detected by immunoblot assay. We purified some of these pro-proteins in small scale using Ni-column. Our PSA-specific fusion proteins are highly toxic for the PSA-expressing LNCaP cells but not control cell in vitro. The PSA-specific pro-drug could promote the cellular caspase-3 and caspase-8 activity and repress the tumor cell proliferation. In addition, our previous report showed the up-regulation of CEBPD expression induces the protein levels of CASP8 and CASP3 in LNCaP and PC3 cells. Hence, we developed a perforin-fused prodrug delivery system to deliver Granzyme B and CEBPD in prostate cancer, the combination therapy could achieve the “CEBPD reactivation” in prostate cancer and up-regulate the level of caspase-8 to improve the efficiency of Granzyme B. Our results of protease specific pro-drug indicate that the combination therapy with prodrugs of Granzyme B and CEBPD could enhances the caspase 8 and caspase 3 activity in the targeting cells to induce the apoptosis and to represses prostate cancer cells proliferation. Based on these results, we successfully developed the real-time cancer and prognosis imaging and therapy system would be very beneficial to the cancer patients and add great convenience to clinical practice.
論文目次 Abstract……………………………………………………………………Ⅰ
中文摘要………………………………………………………………………Ⅱ
誌謝…………………………………………………………………………………Ⅲ
Contents……………………………………………………………………Ⅳ
Abbreviations………………………………………………………Ⅴ

Chapter 1. Introduction………………………………………………1
Chapter 2. Materials and methods………………………13
Chapter 3. Results……………………………………………………………23
3-1. The protease specific imaging probe for cancer detection……………………………………………………………………………………23
3-2. The protease specific probe for imaging the intra-cellular protease
activity………………………………………………………………….…28
3-3. The protease specific protein-drug delivery systems for targeting cancer therapy…………………………………31

Chapter 4. Discussion……………………………………………………36
Reference…………………………………………………………………….………….43
Figures and legends…………………………………………………………53
Publication…………………………………………………………………………….79
Appendix………………………………………………………………………………………80
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