壹、巰嘌呤誘導單層二硫化鉬奈米點螢光淬熄：應用於穀胱甘肽感測、細胞成像，與榖胱甘肽觸發藥物傳遞：
具備表面硫原子空乏缺陷 ( Sulfur vacancies, S-vacancies ) 的二硫化鉬奈米點 ( MoS2 NDs ) 已於過去文獻中被證實可與硫醇分子藉由化學吸附過程進行結合。然而，至今為止，硫醇分子誘導 MoS2 NDs 螢光淬熄的相關研究應用為數相當稀少；因此，我們以巰嘌呤 ( 6-mercaptopurine, 6-MP ) 對水溶液中具有高強度光致螢光放射的單層二硫化鉬奈米點 ( M-MoS2 NDs ) 作為高效的螢光淬熄劑，進行相關範疇的研究報告。6-MP 會藉由分子末端巰基結合於 M-MoS2 NDs 表面的 S-vacancies 上，形成 6-MP-M-MoS2 NDs，再藉由受體-激發光誘導電子轉移機制 ( Acceptor-excited photoinduced electron transfer, acceptor-excited PET )，使 M-MoS2 NDs 發生顯著的螢光淬熄效果。此外，我們發現穀胱甘肽 ( Glutathione, GSH ) 可以有效地觸發 6-MP 自 6-MP-M-MoS2 NDs 表面上被釋放，促使 M-MoS2 NDs 被 6-MP 淬熄的螢光強度大幅回升；於是，我們以 6-MP-M-MoS2 NDs 作為兼具選擇性與高靈敏度的 GSH 螢光強度回升 ( Switched-on ) 形式感測器，應用於紅血球與細胞內 GSH 偵測，其偵測極限達 30 nM。循上述機制，當搭載有巰基化阿黴素 ( Thiolated doxorubicin, DOX-SH ) 的 M-MoS2 NDs ( DOX-SH/M-MoS2 NDs ) 存在於含有 5 mM GSH 的水溶液中時，DOX-SH 會被大量釋放，這表示 DOX-SH/M-MoS2 NDs 可作為對 GSH 響應之奈米載體應用於 DOX-SH 傳遞；更進一步地，我們利用雷射掃描共軛焦螢光顯微鏡與活體分子影像系統分別證實細胞與生物體內 GSH 誘導 DOX-SH 自 DOX-SH/M-MoS2 NDs 表面被釋放之行為。總而言之，基於 M-MoS2 NDs 的螢光放光具有激發光波長依憑之特性，DOX-SH/M-MoS2 NDs 可望作為多功能奈米載體材料，同時應用於藥物傳遞與細胞成像監測。

貳、合成適體功能化二硫化鉬奈米片作為螢光比率探針應用於鉀離子感測與成像
鉀離子 ( Potassium ions, K+ ) 是人類必須營養中的一種宏量元素，也是動物細胞中最主要的金屬陽離子。K+ 對人體生理功能而言，主要是透過調節細胞膜的正常電位差，進一步維持人體生理狀態之恆定性與穩定性；倘若人體 K+ 濃度失調將導致人體產生不適甚至造成性命威脅。二硫化鉬奈米片 ( MoS2 nanosheets, MoS2 NSs ) 具有各項材料優勢，如：良好的人體降解抗性、高核酸親和力、易使細胞攝入，與低細胞毒性等，故我們於本研究中發展出以 MoS2 NSs 作為載體，以配體結合方式 ( Ligand conjugation ) 搭載巰基化寡核苷酸 ( cDNA-SH )。將與 cDNA-SH 部分序列互補，且於兩端修飾有互為螢光共振能量轉移 ( Förster resonance energy transfer, FRET ) 供體 ( Donor) 與受體 ( Acceptor ) 螢光團之對 K+ 具特異性適體 ( D-Apt-A ) 進行雙股雜合 ( D-Apt-A/cDNA-SH )，進一步將適體螢光探針修飾於 MoS2 NSs 上，成功合成 D-Apt-A/cDNA-SH-MoS2 NSs。以 D-Apt-A/cDNA-SH-MoS2 NSs 作為奈米螢光感測探針，利用高效的 FRET 機制誘導雙螢光團產生螢光強度比值為基礎，針對人體血清中 K+ 濃度進行專一性且高靈敏度的偵測應用，偵測極限達 0.3 mM；此外，以雷射掃描共軛焦螢光顯微鏡證實 D-Apt-A/cDNA-SH-MoS2 NSs 可對細胞中 K+ 進行濃度評估與成像。總而言之，我們合理認為 D-Apt-A/cDNA-SH-MoS2 NSs 可作為奈米螢光感測探針，對於許多牽涉到 K+ 的生物體生理調節或生理功能過程進行監測相關應用。

(I) 6-Mercaptopurine-induced fluorescence quenching of monolayer MoS2 nanodots: applications to glutathione sensing, cellular imaging, and glutathione-stimulated drug delivery

Molybdenum disulfide (MoS2) nanodots (NDs) with sulfur vacancies have been demonstrated to be suitable to conjugate thiolated molecules. However, thiol-induced fluorescence quenching of MoS2 NDs has been rarely explored. In this study, 6-mercaptopurine (6-MP) served as an efficient quencher for monolayer MoS2 (M-MoS2) NDs that were highly fluorescent in an aqueous solution. 6-MP molecules were chemically adsorbed at the sulfur vacancy sites of the M-MoS2 NDs. The formed complexes triggered the efficient fluorescence quenching of the M-MoS2 NDs due to acceptor-excited photoinduced electron transfer. The presence of glutathione (GSH) efficiently triggered the release of 6-MP from the M-MoS2 NDs, thereby switching on the fluorescence of the M-MoS2 NDs. Thus, the 6-MP-M-MoS2 NDs were implemented as a platform for the sensitive and selective detection of GSH in erythrocytes and live cells without the interference of cysteine. Additionally, thiolated doxorubicin (DOX-SH)-loaded M-MoS2 NDs (DOX-SH/M-MoS2 NDs) efficiently liberated DOX-SH in the presence of 5 mM GSH, indicating that the DOX-SH/M-MoS2 NDs served as GSH-responsive nanocarriers for DOX-SH delivery. In vivo studies revealed that the DOX-SH/M-MoS2 NDs exhibited efficient uptake by HeLa cells and greater cytotoxicity than free DOX-SH. Intracellular and in vivo GSH-induced release of DOX-SH from DOX-SH-loaded M-MoS2 NDs was further validated by confocal laser scanning microscopy and IVIS spectrum system, respectively. Given the excitation- dependent fluorescence behavior of the M-MoS2 NDs, the DOX-SH/M-MoS2 NDs could be implemented for simultaneous drug delivery and cellular imaging.

(II) Functionalization of MoS2 nanosheets with aptamer as FRET-based nanoprobe for potassium ions sensing and imaging

The potassium ion plays an important role in many physiological functions such as systemic blood pressure control, homeostasis in the muscle, glucose and insulin metabolism, and hyperpolarization of neurons, and therefore the development of a method to monitor K+ in a cell is extremely important. Here, we combine MoS2 nanosheets (MoS2 NSs) with a aptamer-based Förster resonance energy transfer (FRET) nano-probe (D-Apt-A/cDNA-SH), we designed a novel ratiometric fluorescent nanoprobe, termed as an “D-Apt-A/cDNA-SH-MoS2 NSs”, for sensing and imaging K+ concentration values in human serum and living cells, respectively. The D-Apt-A/cDNA-SH-MoS2 NSs consist of a MoS2 NSs, thiolated single-stranded oligonucleotides (cDNA-SH), and dual-dye-labeled aptamer, while FAM conduct as FRET donor (D) and TAMRA (A) as acceptor (D-Apt-A). The cDNA-SH are designed to bind with the D-Apt-A and immobilized on the MoS2 NSs surface via an ligand conjugation. In the absence of target K+, the D-Apt-A are captured by seized with the cDNA-SH, increasing the distance of FAM and TAMRA, inducing a very low FRET efficiency. In this state, only the fluorescence of FAM can be detected. However, in the presence of target K+, the D-Apt-A are gradually replaced from the cDNA-SH, then forming G-quadruplex structures that induce FAM and TAMRA move into closer position with each other, and result in a high FRET efficiency. In this state, the fluorescence of the TAMRA can be clearly detected. Thus, the intensity of fluorescence ratio of acceptor to donor (IFA/IFD) can be used as a signal for detection of target K+.

論文審定書 i
論文公開授權書 ii
摘要 iii
Abstract v
目錄 ix
圖目錄 xi
表目錄 xiii
壹、巰嘌呤誘導單層二硫化鉬奈米點螢光淬熄：應用於穀胱甘肽感測、細胞成像，與榖胱甘肽觸發藥物傳遞 1
1.1 前言 1
1.2 實驗部分 4
1.2.1 實驗藥品 4
1.2.2 儀器設備 6
1.2.3 合成單層二硫化鉬奈米點 7
1.2.4 合成氧化石墨烯 8
1.2.5 單層二硫化鉬奈米點結合硫醇類藥物分子 8
1.2.6 以巰嘌呤-單層二硫化鉬奈米點作為榖胱甘肽螢光感測器 9
1.2.7 穀胱甘肽誘導巰基化阿黴素/單層二硫化鉬奈米點藥物釋放行為 10
1.2.8 細胞存活率分析 11
1.2.9 細胞培養、標記，與藥物傳遞 11
1.3 結果與討論 14
1.3.1 合成並鑑定單層二硫化鉬奈米點 14
1.3.2 巰嘌呤誘導單層二硫化鉬奈米點螢光淬熄 31
1.3.3 以巰嘌呤修飾單層二硫化鉬奈米點作為穀胱甘肽螢光感測器 39
1.3.4 生物體外及細胞內穀胱甘肽觸發單層二硫化鉬奈米點釋放藥物 47
1.3.5 生物體內穀胱甘肽觸發單層二硫化鉬奈米點釋放藥物 57
1.4 結論 59
1.5 參考資料 60
貳、合成適體功能化二硫化鉬奈米片作為螢光比率探針應用於鉀離子感測與成像 68
2.1 前言 68
2.2 實驗部分 71
2.2.1 實驗藥品 71
2.2.2 儀器設備 72
2.2.4 結合適體螢光探針與二硫化鉬奈米片 74
2.2.5 定量錨定於二硫化鉬奈米片表面的寡核苷酸數量 74
2.2.6 以適體螢光探針-二硫化鉬奈米片感測鉀離子 75
2.2.7 細胞毒性測試 76
2.2.8 以適體螢光探針-二硫化鉬奈米片對細胞內鉀離子成像 77
2.3 結果與討論 79
2.3.1 合成並鑑定二硫化鉬奈米片 79
2.3.2 合成並鑑定適體螢光探針-二硫化鉬奈米片 86
2.3.3 以適體螢光探針-二硫化鉬奈米片利用螢光比率法偵測鉀離子 96
2.3.4 以適體螢光探針-二硫化鉬奈米片對細胞內鉀離子成像 105
2.4 結論 107
2.5 參考資料 108

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