奈米藥物載體有助於提高抗癌藥物的傳輸效率，進而改善治療功效與降低副作用，然而現今在評估新開發奈米藥物的療效時，多數僅依賴觀察腫瘤大小與實驗動物的存活率，與搭配腫瘤組織內的載體總累積含量來評估藥物的傳輸情形，因此往往高估載體藥物的有效濃度與低估藥物本身的治療效果。為了克服上述難題，本研究分別結合抽壓導管取樣串連鐵氟龍管分離裝置與感應耦合電漿質譜儀，以及微透析取樣串連線上序列酵素衍生化程序與螢光分析儀，針對監測小鼠腫瘤組織間液內奈米藥物載體及指標性物種的分析需求，發展具有快速、連續與動態分析能力的自動化連線分析平台。
在完成上述連線分析系統的最佳化探討與系統效能驗證之後，本研究針對小鼠腫瘤組織細胞間液內之金奈米粒子藥物載體，進行線上連續偵測的工作，實驗結果顯示經聚二乙醇修飾之金奈米粒子確實有較好的癌細胞標定能力。此外，在針對小鼠腫瘤組織細胞間液中各項生理參數的分析監測上，本研究亦已完成開發可同時監控過氧化氫、乳酸與葡萄糖的線上螢光衍生化連線分析系統，用來觀測經原位注射刺激後，過氧化氫、乳酸與葡萄糖濃度的動態變化情形；上述結果亦說明本研究所建立的二套連線分析系統，確實具有監測活體動物腫瘤組織間液中金奈米粒子、過氧化氫、乳酸與葡萄糖動態變化趨勢的能力，預期藉由整合上述兩個新穎的線上分析系統，可為奈米藥物載體在藥物動力學與藥效動力學的量測上，提供嶄新的跨領域思維及技術平台。
 

Nano-sized drug carriers are capable of improving the transportation efficiency of anticancer drugs as well as reducing the therapeutic side effects. However, the efficacies of these newly developed candidates are so far assessed usually by observing the tumor volumes and the survival rate of treated animals, and their totally accumulated amounts in the whole tumor tissues. To overcome these limitations, we have constructed two novel analytical systems for online continuous monitoring of tumor extracellular gold nanoparticles (AuNPs), hydrogen peroxide (H2O2), lactate, and glucose in living mice by means of (i) combining push–pull perfusion (PPP) sampling, open-tubular fractionation scheme with inductively coupled plasma mass spectrometer, and (ii) hyphenating microdialysis sampling, sequentially enzymatic derivatization with online fluorescence spectrometer. After method’s optimization and validation, our acquired dynamic profiles not only indicated that the pegylated AuNPs had greater tendency toward extravasating into the tumor extracellular space but also revealed that our system possessed the ability to online sequentially determine the concentrations of the tumor extracellular H2O2, lactate, and glucose. Through combining these two online analytical systems, we believe that our integrated analytical platform can provide the new perspectives for in vivo studying the pharmacokinetics and pharmacodynamics of nano-sized drug carriers in future cancer diagnosis and therapeutic applications.

1. 世界衛生組織（World Health Organization，WHO），http://www.who.int/.
2. Morbidity and Mortality Weekly Report（MMWR）. 2013.
3. 台灣行政院衛生福利部國民健康署. 民國102年主要死因分析. 2014.
4. World Cancer Report. 2014.
5. MedicineNet, Inc. - Ow1ned and Operated by WebMD and Part of the WebMD Network，http://www.medicinenet.com/.
6. 歐洲奈米技術平台（European Technology Platform on Nanomedicine，ETP）， http://www.etp-nanomedicine.eu/.
7. Doll, R.; Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 1981, 66, 1192-1308.
8. Colditz, G. A.; Sellers, T. A.; Trapido, E. Epidemiology—identifying the causes and preventability of cancer? Nature Reviews Cancer 2006, 6, 75-83.
9. Cho, K.; Wang, X.; Nie, S.; Shin, D. M. Therapeutic nanoparticles for drug delivery in cancer. Clinical Cancer Research 2008, 14, 1310-1316.
10. McNeil, S. E. Nanotechnology for the biologist. Journal of Leukocyte Biology 2005, 78, 585-594.
11. Liu, Y.; Miyoshi, H.; Nakamura, M. Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. International Journal of Cancer 2007, 120, 2527-2537.
12. Pillai, G. Nanomedicines for cancer therapy: An update of FDA approved and those under various stages development. SOJ Pharmacy & Pharmaceutical Sciences 2014, 1, 1-13.
13. Barenholz, Y. C. Doxil®—the first FDA-approved nano-drug: lessons learned. Journal of Controlled Release 2012, 160, 117-134.
14. Gabizon, A.; Catane, R.; Uziely, B.; Kaufman, B.; Safra, T.; Cohen, R.; Martin, F.; Huang, A.; Barenholz, Y. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Research 1994, 54, 987-992.
15. Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2007, 2, 751-760.
16. Qiao, W.; Wang, B.; Wang, Y.; Yang, L.; Zhang, Y.; Shao, P. Cancer therapy based on nanomaterials and nanocarrier systems. Journal of Nanomaterials 2010, 2010, 7.
17. Hu, C.-M. J.; Aryal, S.; Zhang, L. Nanoparticle-assisted combination therapies for effective cancer treatment. Therapeutic Delivery 2010, 1, 323-334.
18. Meibohm, B.; Derendorf, H. Pharmacokinetics and pharmacodynamics of biotech drugs. Encyclopedia of Molecular Cell Biology and Molecular Medicine 2006.
19. 林山陽，台北榮民總醫院，藥品生體利用率與臨床療效，191-203.
20. Gillies, R. J.; Raghunand, N.; Karczmar, G. S.; Bhujwalla, Z. M. MRI of the tumor microenvironment. Journal of Magnetic Resonance Imaging 2002, 16, 430-450.
21. Jain, R. K. Transport of molecules in the tumor interstitium: a review. Cancer Research 1987, 47, 3039-3051.
22. Vaupel, P. Tumor microenvironmental physiology and its implications for radiation oncology. Seminars in Radiation Oncology 2004, 14, 198-206.
23. Stubbs, M.; McSheehy, P. M.; Griffiths, J. R.; Bashford, C. L. Causes and consequences of tumour acidity and implications for treatment. Molecular Medicine Today 2000, 6, 15-19.
24. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005, 307, 58-62.
25. Bergers, G.; Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nature Reviews Cancer 2003, 3, 401-410.
26. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Medicine 2000, 6, 389-396.
27. Yancopoulos, G. D.; Davis, S.; Gale, N. W.; Rudge, J. S.; Wiegand, S. J.; Holash, J. Vascular-specific growth factors and blood vessel formation. Nature 2000, 407, 242-248.
28. Naumov, G. N.; Akslen, L. A.; Folkman, J. Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell cycle 2006, 5, 1779-1787.
29. Heldin, C.-H.; Rubin, K.; Pietras, K.; Östman, A. High interstitial fluid pressure—an obstacle in cancer therapy. Nature Reviews Cancer 2004, 4, 806-813.
30. Torchilin, V. P. Drug targeting. European Journal of Pharmaceutical Sciences 2000, 11, S81-S91.
31. Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Research 1986, 46, 6387-6392.
32. Maeda, H.; Bharate, G.; Daruwalla, J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. European Journal of Pharmaceutics and Biopharmaceutics 2009, 71, 409-419.
33. Feron, O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology 2009, 92, 329-333.
34. Trédan, O.; Galmarini, C. M.; Patel, K.; Tannock, I. F. Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute 2007, 99, 1441-1454.
35. Ciavarella, S.; Milano, A.; Dammacco, F.; Silvestris, F. Targeted therapies in cancer. BioDrugs 2010, 24, 77-88.
36. Ernsting, M. J.; Murakami, M.; Roy, A.; Li, S.-D. Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. Journal of Controlled Release 2013, 172, 782-794.
37. Brigger, I.; Dubernet, C.; Couvreur, P. Nanoparticles in cancer therapy and diagnosis. Advanced Drug Delivery Reviews 2002, 54, 631-651.
38. Iyer, A. K.; Khaled, G.; Fang, J.; Maeda, H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discovery Today 2006, 11, 812-818.
39. Danhier, F.; Feron, O.; Préat, V. To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release 2010, 148, 135-146.
40. Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nature Reviews Cancer 2002, 2, 750-763.
41. Smith, B. R.; Zavaleta, C.; Rosenberg, J.; Tong, R.; Ramunas, J.; Liu, Z.; Dai, H.; Gambhir, S. S. High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model. Nano Today 2013, 8, 126-137.
42. Cheng, S.-H.; Li, F.-C.; Souris, J. S.; Yang, C.-S.; Tseng, F.-G.; Lee, H.-S.; Chen, C.-T.; Dong, C.-Y.; Lo, L.-W. Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy. ACS Nano 2012, 6, 4122-4131.
43. Lammers, T.; Kiessling, F.; Hennink, W. E.; Storm, G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. Journal of Controlled Release 2012, 161, 175-187.
44. Taurin, S.; Nehoff, H.; Greish, K. Anticancer nanomedicine and tumor vascular permeability; where is the missing link? Journal of Controlled Release 2012, 164, 265-275.
45. Park, K. Facing the truth about nanotechnology in drug delivery. ACS Nano 2013, 7, 7442-7447.
46. Reynolds, T. Y.; Rockwell, S.; Glazer, P. M. Genetic instability induced by the tumor microenvironment. Cancer Research 1996, 56, 5754-5757.
47. Martinez-Outschoorn, U. E.; Lin, Z.; Trimmer, C.; Flomenberg, N.; Wang, C.; Pavlides, S.; Pestell, R. G.; Howell, A.; Sotgia, F.; Lisanti, M. P. Cancer cells metabolically" fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle 2011, 10, 2504-2520.
48. Lisanti, M. P.; Martinez-Outschoorn, U. E.; Lin, Z.; Pavlides, S.; Whitaker-Menezes, D.; Pestell, R. G.; Howell, A.; Sotgia, F. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: The seed and soil also needs" fertilizer". Cell Cycle 2011, 10, 2440-2449.
49. Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery 2009, 8, 579-591.
50. Szatrowski, T. P.; Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Research 1991, 51, 794-798.
51. Chen, Q.; Espey, M. G.; Krishna, M. C.; Mitchell, J. B.; Corpe, C. P.; Buettner, G. R.; Shacter, E.; Levine, M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proceedings of the National Academy of Sciences 2005, 102, 13604-13609.
52. Chen, Q.; Espey, M. G.; Sun, A. Y.; Pooput, C.; Kirk, K. L.; Krishna, M. C.; Khosh, D. B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proceedings of the National Academy of Sciences 2008, 105, 11105-11109.
53. López-Lázaro, M. Dual role of hydrogen peroxide in cancer: possible relevance to cancer chemoprevention and therapy. Cancer Letters 2007, 252, 1-8.
54. Nelson,D.L. Lehninger Principles of Biochemistry. W.H. Freeman 2008.
55. López-Lázaro, M. The Warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen?. Anti-cancer Agents in Medicinal Chemistry 2008, 8, 305–312.
56. Pedersen, P. L. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, ie, elevated glycolysis in the presence of oxygen. Journal of Bioenergetics and Biomembranes 2007, 39, 211-222.
57. Hirschhaeuser, F.; Sattler, U. G.; Mueller-Klieser, W. Lactate: a metabolic key player in cancer. Cancer Research 2011, 71, 6921-6925.
58. Serganova, I.; Rizwan, A.; Ni, X.; Thakur, S. B.; Vider, J.; Russell, J.; Blasberg, R.; Koutcher, J. A. Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype. Clinical Cancer Research 2011, 17, 6250-6261.
59. Walenta, S.; Mueller-Klieser, W. F. Lactate: mirror and motor of tumor malignancy. Seminars in Radiation Oncology 2004, 14, 267-274.
60. Seyfried, T. N.; Flores, R. E.; Poff, A. M.; D’Agostino, D. P. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 2014, 35, 515-527.
61. Vander Heiden, M. G.; Cantley, L. C.; Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324, 1029-1033.
62. Polet, F.; Feron, O. Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. Journal of Internal Medicine 2013, 273, 156-165.
63. Hobbs, S. K.; Monsky, W. L.; Yuan, F.; Roberts, W. G.; Griffith, L.; Torchilin, V. P.; Jain, R. K. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proceedings of the National Academy of Sciences 1998, 95, 4607-4612.
64. Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Advanced Drug Delivery Reviews 2011, 63, 136-151.
65. Gao, J.; Chen, K.; Xie, R.; Xie, J.; Lee, S.; Cheng, Z.; Peng, X.; Chen, X. Ultrasmall near‐infrared non‐cadmium quantum dots for in vivo tumor imaging. Small 2010, 6, 256-261.
66. Diagaradjane, P.; Orenstein-Cardona, J. M.; Colón-Casasnovas, N. E.; Deorukhkar, A.; Shentu, S.; Kuno, N.; Schwartz, D. L.; Gelovani, J. G.; Krishnan, S. Imaging epidermal growth factor receptor expression in vivo: pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe. Clinical Cancer Research 2008, 14, 731-741.
67. Gao, X.; Cui, Y.; Levenson, R. M.; Chung, L. W.; Nie, S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nature Biotechnology 2004, 22, 969-976.
68. Ye, Y.; Chen, X. Integrin targeting for tumor optical imaging. Theranostics 2011, 1, 102.
69. Smith, A. M.; Duan, H.; Mohs, A. M.; Nie, S. Bioconjugated quantum dots for in vivo molecular and cellular imaging. Advanced Drug Delivery Reviews 2008, 60, 1226-1240.
70. Choi, H. S.; Ashitate, Y.; Lee, J. H.; Kim, S. H.; Matsui, A.; Insin, N.; Bawendi, M. G.; Semmler-Behnke, M.; Frangioni, J. V.; Tsuda, A. Rapid translocation of nanoparticles from the lung airspaces to the body. Nature Biotechnology 2010, 28, 1300-1303.
71. Liu, Z.; Cai, W.; He, L.; Nakayama, N.; Chen, K.; Sun, X.; Chen, X.; Dai, H. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nature Nanotechnology 2007, 2, 47-52.
72. Ducongé, F.; Pons, T.; Pestourie, C.; Hérin, L.; Thézé, B.; Gombert, K.; Mahler, B.; Hinnen, F.; Kühnast, B.; Dollé, F. Fluorine-18-labeled phospholipid quantum dot micelles for in vivo multimodal imaging from whole body to cellular scales. Bioconjugate Chemistry 2008, 19, 1921-1926.
73. Lacerda, L.; Soundararajan, A.; Singh, R.; Pastorin, G.; Al-Jamal, K. T.; Turton, J.; Frederik, P.; Herrero, M. A.; Li, S.; Bao, A. Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary excretion. Advanced Materials 2008, 20, 225.
74. Aboagye, E. O.; Price, P. M.; Jones, T. In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discovery Today 2001, 6, 293-302.
75. Yang, R. S.; Chang, L. W.; Wu, J.-P.; Tsai, M.-H.; Wang, H.-J.; Kuo, Y.-C.; Yeh, T.-K.; Yang, C. S.; Lin, P. Persistent tissue kinetics and redistribution of nanoparticles, quantum dot 705, in mice: ICP-MS quantitative assessment. Environmental Health Perspectives 2007, 1339-1343.
76. Elzey, S.; Tsai, D.-H.; Rabb, S. A.; Lee, L. Y.; Winchester, M. R.; Hackley, V. A. Quantification of ligand packing density on gold nanoparticles using ICP-OES. Analytical and Bioanalytical Chemistry 2012, 403, 145-149.
77. Huo, S.; Ma, H.; Huang, K.; Liu, J.; Wei, T.; Jin, S.; Zhang, J.; He, S.; Liang, X.-J. Superior penetration and retention behavior of 50 nm gold nanoparticles in tumors. Cancer Research 2013, 73, 319-330.
78. Bae, Y. H.; Park, K. Targeted drug delivery to tumors: myths, reality and possibility. Journal of Controlled Release 2011, 153, 198.
79. Kim, P.; Yun, S. H.: Intravital microscopy analysis. Encyclopedia of Nanotechnology 2012, 1162-1172.
80. Amornphimoltham, P.; Masedunskas, A.; Weigert, R. Intravital microscopy as a tool to study drug delivery in preclinical studies. Advanced Drug Delivery Reviews 2011, 63, 119-128.
81. Liu, P.; Zhang, A.; Zhou, M.; Xu, Y.; Xu, L. X. Real time 3D detection of nanoparticle liposomes extravasation using laser confocal microscopy. Engineering in Medicine and Biology Society 2004, 1, 2662-2665.
82. Smith, B. R.; Cheng, Z.; De, A.; Rosenberg, J.; Gambhir, S. S. Dynamic visualization of RGD‐Quantum dot binding to tumor neovasculature and extravasation in multiple living mouse models using intravital microscopy. Small 2010, 6, 2222-2229.
83. Smith, B. R.; Kempen, P.; Bouley, D.; Xu, A.; Liu, Z.; Melosh, N.; Dai, H.; Sinclair, R.; Gambhir, S. S. Shape matters: intravital microscopy reveals surprising geometrical dependence for nanoparticles in tumor models of extravasation. Nano Letters 2012, 12, 3369-3377.
84. Vakoc, B. J.; Lanning, R. M.; Tyrrell, J. A.; Padera, T. P.; Bartlett, L. A.; Stylianopoulos, T.; Munn, L. L.; Tearney, G. J.; Fukumura, D.; Jain, R. K. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nature Medicine 2009, 15, 1219-1223.
85. Denk, W.; Strickler, J. H.; Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 1990, 248, 73-76.
86. Andresen, V.; Alexander, S.; Heupel, W.-M.; Hirschberg, M.; Hoffman, R. M.; Friedl, P. Infrared multiphoton microscopy: subcellular-resolved deep tissue imaging. Current Opinion in Biotechnology 2009, 20, 54-62.
87. Schenke-Layland, K.; Riemann, I.; Damour, O.; Stock, U. A.; König, K. Two-photon microscopes and in vivo multiphoton tomographs—powerful diagnostic tools for tissue engineering and drug delivery. Advanced Drug Delivery Reviews 2006, 58, 878-896.
88. Seynhaeve, A. L.; Dicheva, B. M.; Hoving, S.; Koning, G. A.; ten Hagen, T. L. Intact Doxil is taken up intracellularly and released doxorubicin sequesters in the lysosome: evaluated by in vitro/in vivo live cell imaging. Journal of Controlled Release 2013, 172, 330-340.
89. Jain, R. K.; Munn, L. L.; Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nature Reviews Cancer 2002, 2, 266-276.
90. Walenta, S.; Wetterling, M.; Lehrke, M.; Schwickert, G.; Sundfør, K.; Rofstad, E. K.; Mueller-Klieser, W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Research 2000, 60, 916-921.
91. Guo, H.; Aleyasin, H.; Dickinson, B. C.; Haskew-Layton, R. E.; Ratan, R. R. Recent advances in hydrogen peroxide imaging for biological applications. Cell & Bioscience 2014, 4, 64.
92. Kalyanaraman, B.; Darley-Usmar, V.; Davies, K. J.; Dennery, P. A.; Forman, H. J.; Grisham, M. B.; Mann, G. E.; Moore, K.; Roberts, L. J.; Ischiropoulos, H. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radical Biology and Medicine 2012, 52, 1-6.
93. Lippert, A. R.; Van de Bittner, G. C.; Chang, C. J. Boronate oxidation as a bioorthogonal reaction approach for studying the chemistry of hydrogen peroxide in living systems. Accounts of Chemical Research 2011, 44, 793-804.
94. Zhang, M.; Mao, L. Enzyme-based amperometric biosensors for continuous and on-line monitoring of cerebral extracellular microdialysate. Frontiers in Bioscience: A Journal and Virtual Library 2005, 10, 345-352.
95. Mao, L.; Osborne, P. G.; Yamamoto, K.; Kato, T. Continuous on-line measurement of cerebral hydrogen peroxide using enzyme-modified ring-disk plastic carbon film electrode. Analytical Chemistry 2002, 74, 3684-3689.
96. Qian, L.; Yang, X. Composite film of carbon nanotubes and chitosan for preparation of amperometric hydrogen peroxide biosensor. Talanta 2006, 68, 721-727.
97. Wang, J. Electrochemical glucose biosensors. Chemical Reviews 2008, 108, 814-825.
98. Clark, L. C.; Lyons, C. Electrode systems for continuous monitoring in cardiovascular surgery. Annals of the New York Academy of Sciences 1962, 102, 29-45.
99. Cash, K. J.; Clark, H. A. Nanosensors and nanomaterials for monitoring glucose in diabetes. Trends in Molecular Medicine 2010, 16, 584-593.
100. Mizutani, F.; Yabuki, S.; Hirata, Y. Amperometric L-lactate-sensing electrode based on a polyion complex layer containing lactate oxidase. Application to serum and milk samples. Analytica Chimica Acta 1995, 314, 233-239.
101. Yao, T.; Kobayashi, N.; Wasa, T. Flow-injection analysis for L-glutamate using immobilized L-glutamate oxidase: comparison of an enzyme reactor and enzyme electrode. Analytica Chimica Acta 1990, 231, 121-124.
102. Baskar, S.; Chang, J.-L.; Zen, J.-M. Simultaneous detection of NADH and H2O2 using flow injection analysis based on a bifunctional poly (thionine)-modified electrode. Biosensors and Bioelectronics 2012, 33, 95-99.
103. Perdomo, J.; Hinkers, H.; Sundermeier, C.; Seifert, W.; Morell, O. M.; Knoll, M. Miniaturized real-time monitoring system for L-lactate and glucose using microfabricated multi-enzyme sensors. Biosensors and Bioelectronics 2000, 15, 515-522.
104. Lin, Y.; Liu, K.; Yu, P.; Xiang, L.; Li, X.; Mao, L. A facile electrochemical method for simultaneous and on-line measurements of glucose and lactate in brain microdialysate with prussian blue as the electrocatalyst for reduction of hydrogen peroxide. Analytical Chemistry 2007, 79, 9577-9583.
105. Nandi, P.; Lunte, S. M. Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: a review. Analytica Chimica Acta 2009, 651, 1-14.
106. Ryu, J. H.; Koo, H.; Sun, I.-C.; Yuk, S. H.; Choi, K.; Kim, K.; Kwon, I. C. Tumor-targeting multi-functional nanoparticles for theragnosis: new paradigm for cancer therapy. Advanced Drug Delivery Reviews 2012, 64, 1447-1458.
107. Watson, C. J.; Venton, B. J.; Kennedy, R. T. In vivo measurements of neurotransmitters by microdialysis sampling. Analytical Chemistry 2006, 78, 1391-1399.
108. Ungerstedt, U.; Hallström, Å. In vivo microdialysis-a new approach to the analysis of neurotransmitters in the brain. Life Sciences 1987, 41, 861-864.
109. Torto, N.; Laurell, T.; Gorton, L.; Marko-Varga, G. Recent trends in the application of microdialysis in bioprocesses. Analytica Chimica Acta 1998, 374, 111-135.
110. Elmquist, W. F.; Sawchuk, R. J. Application of microdialysis in pharmacokinetic studies. Pharmaceutical Research 1997, 14, 267-288.
111. Chaurasia, C. S.; Müller, M.; Bashaw, E. D.; Benfeldt, E.; Bolinder, J.; Bullock, R.; Bungay, P. M.; DeLange, E. C.; Derendorf, H.; Elmquist, W. F. AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives report from the Joint AAPS-FDA Workshop, November 4–5, 2005, Nashville, TN. American Association of Pharmaceutical Scientists 2007, 9, E48-E59.
112. Torto, N.; Mwatseteza, J.; Sawula, G. A study of microdialysis sampling of metal ions. Analytica Chimica Acta 2002, 456, 253-261.
113. Snook, R. Handbook of inductively coupled plasma mass spectrometry. Chromatographia 1992, 34, 546-546.
114. Beauchemin, D. Inductively coupled plasma mass spectrometry. Analytical Chemistry 2002, 74, 2873-2894.
115. Todolí, J. L.; Mermet, J. M. Elemental analysis of liquid microsamples through inductively coupled plasma spectrochemistry. TrAC Trends in Analytical Chemistry 2005, 24, 107-116.
116. Guo, X.; Sturgeon, R. E.; Mester, Z.; Gardner, G. J. Vapor generation by UV irradiation for sample introduction with atomic spectrometry. Analytical Chemistry 2004, 76, 2401-2405.
117. Sharp, B. L. Pneumatic nebulisers and spray chambers for inductively coupled plasma spectrometry. A review. Part 1. Nebulisers. Journal of Analytical Atomic Spectrometry 1988, 3, 613-652.
118. Douglas, D. J.; Quan, E. S.; Smith, R. Elemental analysis with an atmospheric pressure plasma (MIP, ICP)/quadrupole mass spectrometer system. Spectrochimica Acta Part B: Atomic Spectroscopy 1983, 38, 39-48.
119. Lackowicz, J. Principle of Fluorescence Spectroscopy, Analytical Chemistry, 2006. Chapter, 1, 10.
120. Education in Microscopy and Digital Imaging, http://zeiss-campus.magnet.fsu.edu/articles/.html.
121. Palmer, C. A.; Loewen, E. G.; Thermo, R. Diffraction grating handbook, Newport Corporation Springfield, 2005.
122. Molecular Fluorescence Spectroscopy, http://elchem.kaist.ac.kr/vt/chem-ed/spec/molec/mol-fluo.htm.
123. Hamamatsu Photonics K.K. Editorial Committee, Handbook of photomultiplier tubes. Hamamatsu Photonics K.K. Electron Tube Division, 2007.
124. Microscopy Resource Center, http://www.olympusmicro.com/index.html.
125. Bihari, P.; Vippola, M.; Schultes, S.; Praetner, M.; Khandoga, A. G.; Reichel, C. A.; Coester, C.; Tuomi, T.; Rehberg, M.; Krombach, F. Optimized dispersion of nanoparticles for biological in vitro and in vivo studies. Particle and Fibre Toxicology 2008, 5, 1-14.
126. Murdock, R. C.; Braydich-Stolle, L.; Schrand, A. M.; Schlager, J. J.; Hussain, S. M. Characterization of nanomaterial dispersion in solution prior to in vitro exposure using dynamic light scattering technique. Toxicological Sciences 2008, 101, 239-253.
127. Sweeney, S. F.; Woehrle, G. H.; Hutchison, J. E. Rapid purification and size separation of gold nanoparticles via diafiltration. Journal of the American Chemical Society 2006, 128, 3190-3197.
128. Schmidt, B.; Loeschner, K.; Hadrup, N.; Mortensen, A.; Sloth, J. J.; Bender Koch, C.; Larsen, E. H. Quantitative characterization of gold nanoparticles by field-flow fractionation coupled online with light scattering detection and inductively coupled plasma mass spectrometry. Analytical Chemistry 2011, 83, 2461-2468.
129. Calzolai, L.; Gilliland, D.; Garcìa, C. P.; Rossi, F. Separation and characterization of gold nanoparticle mixtures by flow-field-flow fractionation. Journal of Chromatography A 2011, 1218, 4234-4239.
130. Al-Somali, A. M.; Krueger, K. M.; Falkner, J. C.; Colvin, V. L. Recycling size exclusion chromatography for the analysis and separation of nanocrystalline gold. Analytical Chemistry 2004, 76, 5903-5910.
131. Brewer, S. H.; Glomm, W. R.; Johnson, M. C.; Knag, M. K.; Franzen, S. Probing BSA binding to citrate-coated gold nanoparticles and surfaces. Langmuir 2005, 21, 9303-9307.
132. De Paoli Lacerda, S.H.; Park, J.J.; Meuse, C.; Pristinski, D.; Becker, M.L.; Karim, A.; Douglas, J.F. Interaction of gold nanoparticles with common human blood proteins. ACS Nano 2010, 4, 365-379.
133. Wang, J.; Hansen, E. H. On-line sample-pre-treatment schemes for trace-level determinations of metals by coupling flow injection or sequential injection with ICP-MS. TrAC Trends in Analytical Chemistry 2003, 22, 836-846.
134. Cellar, N. A.; Burns, S. T.; Meiners, J.-C.; Chen, H.; Kennedy, R. T. Microfluidic chip for low-flow push-pull perfusion sampling in vivo with on-line analysis of amino acids. Analytical Chemistry 2005, 77, 7067-7073.
135. Karakoti, A. S.; Das, S.; Thevuthasan, S.; Seal, S. PEGylated inorganic nanoparticles. Angewandte Chemie International Edition 2011, 50, 1980-1994.
136. Walkey, C. D.; Olsen, J. B.; Guo, H.; Emili, A.; Chan, W. C. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. Journal of the American Chemical Society 2012, 134, 2139-2147.
137. Hirayama, A.; Kami, K.; Sugimoto, M.; Sugawara, M.; Toki, N.; Onozuka, H.; Kinoshita, T.; Saito, N.; Ochiai, A.; Tomita, M. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Research 2009, 69, 4918-4925.