臺灣博碩士論文加值系統

本實驗結合近紅外光 (NIR) 螢光染料，indocyanine green (ICG)，為一種光敏劑，目前作為體內光學影像近紅外光 (NIR) 造影劑，利用靜電吸引力吸附在由胺根修飾的layered double hydroxide nanoparticles (LDHs)上形成LDHs-ICG，進一步在LDHs-ICG的外層以幾丁聚醣(chitosan)包覆，透過glutaraldehyde (GA)當交聯劑，交叉聯接修飾胺根的LDHs和不同層的幾丁聚醣(chitosan)。這種有機-無機雜合的奈米複合材料使得近紅外光 (NIR) 造影劑有較高的效率，因為LDHs層狀結構可以穩定吸收indocyanine green (ICG)，防止在各種生理條件下分離或代謝。而光敏劑除了作為造影劑，也可應用在光化學動力療法(Photodynamic therapy , PDT)，PDT是利用光敏藥物選擇累積在特定疾病組織的特性，用特定波長的光應用在受影響的區域。實驗結果顯示，經由Chitosan包覆不僅可以防止ICG掉落，以LDHs當載體也可提高對光的穩定性。而由細胞實驗和溶血試驗顯示其有低毒性和低釋放血紅蛋白量。在生物體內分佈方面，LDHs包覆不同層的幾丁聚醣(chitosan)不僅使藥物釋放到特定的器官，也可有效的累積在不同的標的器官。未包覆的LDHs-ICG是累積在肝臟和脾臟；包覆一層的LDHs-ICG累積在肺；包覆兩層的LDHs-ICG則累積在肝臟和肺部。在光化學動力療法(Photodynamic therapy , PDT)方面，經光照射之後，細胞存活率有下降的趨勢。以2’, 7’- Dichlorodihydrofluorescin diacetate (DCFH-DA)染劑來偵測ROS，結果顯示螢光強度明顯增強，表示LDH-ICG-CS會產生ROS導致細胞凋亡。除了利用幾丁聚醣(chitosan)包覆LDHs-ICG可開發高潛能的體內成像造影劑，也可控制治療藥物準確送達目標器官。因此，藉由這樣的實驗設計，我們希望可以改善傳統的癌症診斷和癌症化療的效率。

We incorporated a near-infrared (NIR) fluorescent dye, indocyanine green (ICG), in amine-modified layered double hydroxide nanoparticles (LDHs) by electrostatic attractions to render LDHs–ICG as an efficient NIR contrast agent for in vivo optical imaging. The further coating of chitosan on the external surfaces of LDHs–ICG was achieved through the cross-linking of amine-modified LDHs and different amounts of chitosan by using glutaraldehyde (GA) as a cross-linked agent. The hybridization of this organic–inorganic nanocomposite produced an efficient NIR optical contrast agent because the adsorbed ICG molecules were stabilized in the layered structures of LDHs to prevent them from leaching and/or metabolizing in the physiological conditions. By this approach, the encapsulation of the photosensitizer in the chitosan-coated LDHs for PDT (Photodynamic therapy) can selectively accumulate on diseased tissues with a light specific wavelength then applied to the affected area for the production of Reactive Oxygen Species (ROS). The cell viability and hemolysis assay also showed low cytotoxicity and low release of hemoglobin from the cell lysis of red blood cells (RBCs). The in vivo bio-distribution results demonstrated that the coating of LDHs with different amounts of chitosan can develop organ-specific drug delivery systems, which can efficiently regulate the nanoparticle accumulation in various organs with un-coated LDHs–ICG targeting the liver and spleen, mono-chitosan-coated LDHs–ICG targeting the lungs, double chitosan-coated LDHs–ICG targeting the lungs and liver, and trimethylammonium (TA) modified double chitosan-coated LDHs–ICG samples targeting the liver. When the colon cancer cells (HT-29) were treated with chitosan-coated LDHs-ICG and then irradiated with near-infrared laser (800 nm), the cell viability showed a large decrease. We also used 2 ',7'- Dichlorodihydrofluorescin diacetate (DCFH - DA) to detect the ROS, with our results showing that the fluorescent intensity was significantly enhanced, indicating that the chitosan-coated LDHs- ICG samples led to apoptosis through the production of intracellular ROS. In addition to the high potential for the employment of chitosan-coated LDHs–ICG samples for developing contrast agents for in vivo imaging, the LDH nanoparticles can deliver therapeutic drugs to the desired target organs by controlling the coating amounts of chitosan. Therefore, this approach can improve efficiency for traditional cancer diagnosis and cancer chemotherapy.

中文摘要 ..................................................... Ⅰ
Abstract ................................ ................... Ⅲ
Table of Contents ........................................... Ⅵ
1. Background ............................................... 1
1.1 Layered double hydroxides (LDHs)......................... 1
1.2 Drug delivery systems (DDS) of Nanoparticles ............ 4
1.3 Photodynamic therapy (PDT) .............................. 6
1.4 Nanoparticles in photodynamic therapy ................... 8
2. Introduction ............................................. 11
3. Experimental Section ..................................... 19
Section Ⅰ .....................................................19
3.1 Materials ............................................... 19
3.2 Preparation ............................................. 19
3.3 Leaching test ........................................... 22
3.4 Biodistribution studies ................................. 22
3.5 Cytotoxicity assay ...................................... 23
3.6 Cell viability assay .................................... 23
3.7 Hemolysis assay ......................................... 23
3.8 Instrumentation and measurements......................... 24
SectionⅡ..................................................... 26
3.1 Materials ............................................... 26
3.2 Characterization and Instruments ........................ 26
3.3 Synthesis of LDH Nanoparticles .......................... 27
3.4 Synthesis of LDHs–NH2 ................................... 27
3.5 Synthesis of LDHs–NH2–ICG ............................... 28
3.6 Synthesis of Chitosan-Coated LDHs–NH2–ICG ............... 28
3.7 Synthesis of LDH–NH2–FITC–CS ............................ 29
3.8 Photostability Assay .................................... 29
3.9 Cellular Uptake and Imaging by Confocal Microscopy ...... 30
3.10 Lysosome Staining ...................................... 30
3.11 In Vitro Determination of Singlet Oxygen Production by 1,3-Diphenylisobenzofuran (DPBF) ................................ 30
3.12 Photodynamic Effect Measurement......................... 31
3.13 Measurements of the Mitochondrial Membrane Potential.... 31
3.14 Comet Assay ............................................ 32
3.15 Flow Cytometric Detections ............................. 32
3.16 Lactate Dehydrogenase Assay ............................ 33
4. Results and discussion ................................... 35
Section Ⅰ .................................................... 35
4.1 Material characterization ............................... 35
4.2 Stability studies ....................................... 43
4.3 Biodistribution studies ................................. 44
4.4 Cytotoxicity assay ...................................... 46
4.5 Hemolysis assay ......................................... 47
Section Ⅱ ................................................... 49
4.1 Physical Characterization of Chitosan-Coated Layered Double Hydroxide (LDH)–NH2–Indocyanine Green(ICG) Matrix............ 49
4.2 Photostability of ICG in LDH–Chitosan Matrix ............ 51
4.3 Cell Uptake and in Vitro Cell Imaging ................... 52
4.4 Determination of Singlet Oxygen Generation .............. 54
4.5 Phototherapy Assay ...................................... 55
4.6 Apoptosis................................................ 55
5. Conclusions .............................................. 61
6. Figures and Tables ....................................... 63
7. Reference ................................................ 97

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