奈米材料生醫顯影應用

Bio-applications and Bio-imaging of Nanomaterials

陳昱群(Yu-Chun Chen)

指導教授 ： 周必泰

國立臺灣大學/理學院/化學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.00004

摘要

奈米化學這個新興的科學領域，因為相同物質的材料在這個尺寸下展現了和平常不一樣的物理與化學性質，而吸引了非常多的關注。除了在設計與合成許多不同的奈米材料之外，我們也對這些特別結構的應用作更進一步的探討。利用雙光子雷射掃描共軛焦顯微技術的高解析度、核磁共振無與倫比的穿透深度、以及其他分子生物學上的檢測方法，我們對超順磁性氧化鐵、量子點、以及金奈米材料的生物相容性和應用性做調查和評估。

我們發現在利用二氧化矽或是血清蛋白對一般油溶性的奈米材料進行包覆處理以後，大幅的提高了它們的水溶性，化學可修飾性，也同時降低了一般未經處理的奈米材料所造成的生物毒性。當這些奈米材料的生物相容性達到一定水準時，就可以拿能應用在活體上。

本篇論文的第一章介紹利用氧化鐵為核心、二氧化矽為載體、並包覆铱 (Ir)錯合物以達成三合一功能的奈米粒子。其中核心氧化鐵可以提供增強核磁共振，而會受氧淬熄的銥錯合物可同時提供螢光的標定，以及產生單氧殺死子宮頸癌細胞(光動力療法)。第二章介紹包覆在二氧化矽殼的新系列四極雙光子吸收染劑，因為該染劑除了有很強的單光子放光外，在適用於生物體的近紅外光800nm 下有極高 (7000 GM/甲苯)的雙光子吸收。除了利用光學顯微鏡觀察巨噬細胞對該奈米粒子的吞噬，也對其光動力療法的效率做定量的測試。第三章提到使用鐵鉑/氧化鐵奈米架構 (FePt/Fe3O4)，包附在內部的鉑會隨著進入細胞的酸性胞器時被釋放出來，而與細胞核內部的核醣核酸反應殺死細胞。第四章突破性的調整量子點包覆二氧化矽殼後光氧化的時機，同時也將測試生相容性和雙光子顯影的細胞種類從培養容易的癌症或巨噬細胞，轉成取得及培養不易，重要性卻日與具增的人類間質幹細胞。第五章則是目前最熱門的發光奈米金奈米材料，其高效能的單光子與雙光子吸收，以及容易聚集在細胞膜的特性，使其成為極有潛力做為標定幹細胞的染劑。

關鍵字

奈米材料 ； 顯影

並列摘要

Nanochemistry, a new realm in scientific research, has attracted numerous attention as materials at this scale possess different properties compared to their bulk counterparts. In addition to designing and synthesizing nanomaterials of different kind, explorations of applications of these unique structures are conducted. Utilizing the high resolution of two-photon/confocal microscopy, unparallel penetration depth of magnetic resonance imaging (MRI), and other cellular assays, the feasibility and biocompatibility of superparamagnetic iron oxide (SPIOs), quantum dots, and Au nanomaterials are investigated and evaluated.
It was discovered that by coating the hydrophobic nanomaterials with silica or serum albumin, not only the solubility and chemical modification fesibility could be significantly enhanced, but the greatly surpressed cytotoxicity also enable these treated nanomaterials being biocompatible.
The first chapter of the thesis elucidates how a three-in-one nano system was achieved by employing silica as a shell and a template to encapsulate the superparamagnetic iron oxide core and Ir complexes. The iron oxide core served as a MRI contrast agent, whereas the Ir complex, which was prone to oxygen quenching, simultaneously provided sufficient phosphorescence for optical labeling and efficient singlet oxygen generation to induce apotosis of cancer cells (photo dynamic therapy) . Chapter 2 introduces a new series of quadrupolar type two-photon absorption (2PA) chromophores. Taking advantage of the high quantum yield and very large 2PA corss section value (~7,000 GM at 800 nm in toluene) in the region of near infared window, observation of the particles internalization by rat macrophages with light microscopy and quantitative determination of the efficacy of the photo dynamic therapy with cellular assay were successful. Chapter 3 discribes a FePt/Fe3O4 core shell system, which Pt inside the core would be released once entered the acidic organelle of a cell. Pt would eventually interact with the DNA and induce cell death. Chapter 4 illistrates the importance of delaying the photo-oxidation procedsure to recover the emission quenching often encountered when encapsulating quantum dot in silica shells. The cell line employed for toxicity evaluation and labeling has also been switched from common cancer cell lines or marcophages to a more delicate and important human mesenchymal stem cell line. Chapter 5 explores the two-photon induced luminescence of 11-mercaptoundecanoic acid funtionals quantum-sized Au nanodots. The high single and two photon induced emission with high biocompatibility after dextan coating, makes the nano size Au a promising imaging agent for human mesenchymal stem cells.

並列關鍵字

nanomaterials ； bio-imaging

參考文獻

[24] T. Okamoto, T. Aoyama, T. Nakayama, T. Nakamata, T. Hosaka, K. Nishijo, T. Nakamura, T. Kiyono and J. Toguchida, Biochem. Biophys. Res. Commun., 2002, 295, 354

[25] Pu S.-C.; Yang M.-J.; Hsu C.-C.; Lai C.-W.; Hsieh C.-C., Lin S. H.; Cheng Y.-M.; Chou P.-T. Small, 2006, 2, 1308

[7] a) S. Zheng, A. Leclercq, J. Fu, L. Beverina, L. A. Padilha, E. Zojer, K. Schmidt, S. Barlow, J. Luo, S.-H. Jiang, A. K.-Y. Jen, Y. Yi, Z. Shuai, E. W. Van Stryland, D. J. Hagan, J.-L. Bredas, S. R. Marder, Chem. Mater. 2007, 19, 432; b) C. L. Droumaguet, O. Mongin, M. H. V. Werts, M. Blanchard-Desce, Chem. Commun. 2005, 2802; c) B. R. Cho, K. H. Son, S. H. Lee, Y.-S. Song, Y.-K. Lee, S.-J. Jeon, J. H. Choi, H. Lee, M. Cho, J. Am. Chem. Soc. 2001, 123, 10039 ; d) A. Bhaskar, G. Ramakrishna, Z. Lu, R. Twieg, J. M. Hales, D. J. Hagan, E. Van Stryland, T. Goodson III, J. Am. Chem. Soc. 2006, 128, 11840; e) S. Yao, K. D. Belfield, J. Org. Chem. 2005, 70, 5126; f) S. Das, A. Nag, D. Goswami, P. K. Bharadwaj, J. Am. Chem. Soc. 2006, 128, 402; g) M. Samoc, J. P. Morrall, G. T. Dalton, M. P. Cifuentes, M. G. Humphrey, Angew. Chem. Int. Ed. 2007, 46, 731; h) P. Wei, X. Bi, Z. Wu, Z. Xu, Org. Lett. 2005, 7, 3199; i) P.-H. Huang, J.-Y. Shen, S.-C. Pu, Y.-S. Wen, J.-T. Lin, P.-T. Chou, M.-C. P. Yeh, J. Mater. Chem. 2006, 16, 850. j) C.-F. Chou, T.-H. Huang, J. T. Lin, C.-C. Hsieh, C.-H. Lai, P.-T. Chou, C. Tsai, Tetrahedron 2006, 62, 8467.

[14]. (a) H. Mattoussi, J. M. Mauro, E. R. Goldman, G. P. Anderson, V. C. Sundar, F. V. Milkulec and M. G. Bawendi, J. Am. Chem. Soc. 2000, 122, 12142; (b) C. -Y. Chen, C. -T. Cheng, C. -W. Lai, P. -W. Wu, K. -C. Wu, P. -T. Chou, Y. -H. Chou, H.. -T. Chiu, Chem. Commun. 2006, 263.

[3] (a)S. Kim, B. Fisher, H. J. Eisler, M. G. Bawendi, J. Am. Chem. Soc. 2003, 125, 11466. (b)C. -Y. Chen, C. -T. Cheng, J. -K. Yu, S. -C. Pu, Y. -M. Cheng, P. -T. Chou, Y. -H. Chou, H. -T. Chiu, J. Phys. Chem. B 2004, 108, 10687; (c) P. -T. Chou, C. -Y. Chen, C. T. Cheng, S. -C. Pu, K. -C. Wu, Y. -M. Cheng, C. -W. Lai, Y. -H. Chou, H. -T. Chiu, ChemPhysChem. 2006, 7, 222; (d) B. Blackman, D. M. Battaglia, T. D. Mishima, M. B.Johnson, X. G. Peng, Chem. Mater. 2007, 19, 3815; (e) C. -Y. Chen, C. -T. Cheng, C. -W. Lai, Y. -H. Hu, P. -T. Chou, Y. -H. Chou, H. -T. Chiu, Small 2005, 1, 1215; (f) C. -Y. Chen, C. -T. Cheng, J. -K. Yu, S. -C. Pu, Y. -M. Cheng, P. -T. Chou, J. Phys. Chem. B 2004, 108, 10687 ; (g) C. -T. Cheng,; C. -Y. Chen, C. -W. Lai,; W.-H. Liu,; S. -C. Pu, P. -T. Chou, Y. -H. Chou, H. -T. Chiu, J. Mater. Chem. 2005, 15, 3409.