本研究使用葉酸做為還原劑及保護劑，以加熱法一步驟合成出葉酸-奈米金，研究結果發現當還原劑葉酸與還原溶液四氯酸金濃度比率為0.56時有較佳的奈米金產率，且葉酸-奈米金的大小形狀較為均勻。除此之外，奈米粒子具有良好的穩定性，其介達電位以及粒徑大小能持續保持在60nm以及-27mV長達35天以上，代表著粒子間有著良好的排斥力，能長時間維持原態。
在細胞攝入實驗中，我們觀察了骨母細胞在骨分化前期以及骨分化中後期對於葉酸-奈米金的攝入機制， 細胞切片的TEM影像顯示，在1天後便可將葉酸-奈米金粒子攝入，在攝入3天後細胞質內葉酸-奈米金含量達最高峰，在3至5天時行胞吐作用排出，除此之外，觀察到分化前後細胞對葉酸-奈米金的攝入時程具有相似的趨勢。
在體外細胞實驗部分發現，30μM的葉酸-奈米金會影響分化，促進鹼性磷酸酶的分泌以及鈣鹽的沉積;而葉酸-奈米金濃度若在20μM以下則不會對細胞活性、細胞分化、蛋白質分泌以及礦化造成影響。
表面增強拉曼散射應用於追蹤細胞分化的結果顯示，使用長波長激發光雷射以及葉酸-奈米金粒子的攝入能有效消除細胞螢光訊號，大幅增強細胞內生物分子的拉曼訊號，其中礦化初期的生物指標氫氧基磷灰石之拉曼訊號強度能增幅至1069%，而其前驅物β-TCP以及DCPD能增幅至217%以及222%。

In this research, folic acid was used as a reducing and protective agent to synthesize gold nanoparticles in a one-step process. The results showed that when the ratio of folic acid and chloroauric acid is 0.56, we can prepare uniform FA-GNPs with high yield. In addition, the nano-particles showed good stability, and the zeta potential and particle size were maintained at 60 nm and -27 mV for more than 35 days. It revealed a repulsive force between particles, preventing the aggregation between particles for a long time.
From TEM images, the cellular uptake of FA-GNPs took about 1 day, and the maximum number of FA-GNPs in cytoplasm was reached after 3 days. After the culture for 3-5 days, the exocytosis of GNPs was observed. No matter before or after the early osteogenic differentiation, progress of FA-GNPs uptake was almost the same.
According to in vitro tests, it was found if the FA-GNPs concentration was less than 30 μM, the cell viability, differentiation, protein secretion, and mineralization was not affected. On the other hand, FA-GNPs which was more concentrated than 30 μM would enhance the cell viability and mineralization.
By using the laser excitation with long wavelength and the cellular uptake of FA-GNPs, the eliminated fluorescence noises was greatly reduced and the Raman signals was highly magnified. Raman intensity of the hydroxyapatite, β-TCP and DCPD was increased by 1069%, 217% and 222%. In addition,the Raman intensity of β-TCP and DCPD,the precursors of hydroxyapatite,can be increased to 217% and 222% individually.The real-time biomineralization was thus proved in situ.

1. Chen, H.M., R.S. Liu, and D.P. Tsai, A Versatile Route to the Controlled Synthesis of Gold Nanostructures. Crystal Growth & Design, 2009. 9: p. 2079-2087.
2. De, M., P.S. Ghosh, and V.M. Rotello, Applications of Nanoparticles in Biology. Advanced Materials, 2008. 20: p. 4225-4241.
3. Rosenstiel, S.F., M.F. Land, and B.J. Crispin, Dental luting agents: A review of the current literature. The Journal of Prosthetic Dentistry, 1998. 80: p. 280-301.
4. Gillibert, R., M. Sarkar, J.F. Bryche, R. Yasukuni, J. Moreau, G. Barbillon, B. Bartenlian, M. Canva, and M.L. Chapelle, Directional surface enhanced Raman scattering on gold nano-gratings. Nanotechnology, 2016. 27: p. 115202-115210.
5. Daniel, M.C. and D. Astruc, Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev, 2004. 104: p. 293-346.
6. Alivisatos, P., The use of nanocrystals in biological detection. Nat Biotech, 2004. 22: p. 47-52.
7. Brewer, S.H., W.R. Glomm, M.C. Johnson, M.K. Knag, and S. Franzen, Probing BSA Binding to Citrate-Coated Gold Nanoparticles and Surfaces. Langmuir, 2005. 21: p. 9303-9307.
8. Lacerda, S.H.D.P., J.J. Park, C. Meuse, D. Pristinski, M.L. Becker, A. Karim, and J.F. Douglas, Interaction of Gold Nanoparticles with Common Human Blood Proteins. ACS Nano, 2010. 4: p. 365-379.
9. Maxwell, D.J., J.R. Taylor, and S. Nie, Self-Assembled Nanoparticle Probes for Recognition and Detection of Biomolecules. Journal of the American Chemical Society, 2002. 124: p. 9606-9612.
10. Turkevich, J., G. Garton, and P.C. Stevenson, The color of colloidal gold. Journal of Colloid Science, 1954. 9: p. 26-35.
11. Frens, G., Controlled nucleation for the regulation of the particle size in monodisperse gold suspensions. Nature Physical Science, 1973. 241: p. 20-22.
12. Jana, N.R., L. Gearheart, and C.J. Murphy, Seed-Mediated Growth Approach for Shape-Controlled Synthesis of Spheroidal and Rod-like Gold Nanoparticles Using a Surfactant Template. Advanced Materials, 2001. 13: p. 1389-1393.
13. Jana, N.R.L.G., S.O. Obare, and C.J. Murphy, Anisotropic Chemical Reactivity of Gold Spheroids and Nanorods. Langmuir, 2002. 18: p. 922-927.
14. Jana, N.R., L. Gearheart, and C.J. Murphy, Wet Chemical Synthesis of High Aspect Ratio Cylindrical Gold Nanorods. The Journal of Physical Chemistry B, 2001. 105: p. 4065-4067.
15. Brust, M., M. Walker, D. Bethell, D.J. Schiffrin, and R. Whyman, Synthesis of thiol-derivatised gold nanoparticles in a two-phase Liquid-Liquid system. Journal of the Chemical Society, Chemical Communications, 1994. 0: p. 801-802.
16. Aslam, M., L. Fu, M. Su, K. Vijayamohanan, and V.P. Dravid, Novel one-step synthesis of amine-stabilized aqueous colloidal gold nanoparticles. Journal of Materials Chemistry, 2004. 14: p. 1795-1797.
17. Norman, T.J., C.D. Grant, D. Magana, J.Z. Zhang, J. Liu, D. Cao, F. Bridges, and A. Van Buuren, Near Infrared Optical Absorption of Gold Nanoparticle Aggregates. The Journal of Physical Chemistry B, 2002. 106: p. 7005-7012.
18. Malikova, N., I. Pastoriza-Santos, M. Schierhorn, N.A. Kotov, and L.M. Liz-Marzán, Layer-by-Layer Assembled Mixed Spherical and Planar Gold Nanoparticles:  Control of Interparticle Interactions. Langmuir, 2002. 18: p. 3694-3697.
19. Sylvestre, J.P., A.V. Kabashin, E. Sacher, M. Meunier, and J.H.T. Luong, Stabilization and Size Control of Gold Nanoparticles during Laser Ablation in Aqueous Cyclodextrins. Journal of the American Chemical Society, 2004. 126: p. 7176-7177.
20. Huang, H. and X. Yang, Synthesis of polysaccharide-stabilized gold and silver nanoparticles: a green method. Carbohydrate Research, 2004. 339: p. 2627-2631.
21. Mittal, A.K., Y. Chisti, and U.C. Banerjee, Synthesis of metallic nanoparticles using plant extracts. Biotechnol Adv, 2013. 31: p. 346-356.
22. Sharma, J., Y. Tai, and T. Imae, Biomodulation approach for gold nanoparticles: synthesis of anisotropic to luminescent particles. Chem Asian J, 2010. 5: p. 70-73.
23. Qian, J., X. Li, M. Wei, X. Gao, Z. Xu, and S. He, Bio-molecule-conjugated fluorescent organically modified silica nanoparticles as optical probes for cancer cell imaging. Optics Express, 2008. 16: p. 19568-19578.
24. Li, G., D. Li, L. Zhang, J. Zhai, and E. Wang, One-Step Synthesis of Folic Acid Protected Gold Nanoparticles and Their Receptor-Mediated Intracellular Uptake. Chemistry – A European Journal, 2009. 15: p. 9868-9873.
25. Sokolov, K., D. Nida, M. Descour, A. Lacy, M. Levy, B. Hall, S. Dharmawardhane, A. Ellington, B. Korgel, and R. Richards‐Kortum, Molecular Optical Imaging of Therapeutic Targets of Cancer. Advances in Cancer Research, 2006. 96: p. 299-344.
26. El-Sayed, I.H., X. Huang, and M.A. El-Sayed, Surface Plasmon Resonance Scattering and Absorption of anti-EGFR Antibody Conjugated Gold Nanoparticles in Cancer Diagnostics:  Applications in Oral Cancer. Nano Letters, 2005. 5: p. 829-834.
27. Veiseh, O., C. Sun, J. Gunn, N. Kohler, P. Gabikian, D. Lee, N. Bhattarai, R. Ellenbogen, R. Sze, A. Hallahan, J. Olson, and M. Zhang, Optical and MRI Multifunctional Nanoprobe for Targeting Gliomas. Nano Letters, 2005. 5: p. 1003-1008.
28. Zhao, W., M.A. Brook, and Y. Li, Design of Gold Nanoparticle-Based Colorimetric Biosensing Assays. ChemBioChem, 2008. 9: p. 2363-2371.
29. Karhanek, M., J.T. Kemp, N. Pourmand, R.W. Davis, and C.D. Webb, , Single DNA Molecule Detection Using Nanopipettes and Nanoparticles. Nano Letters, 2005. 5: p. 403-407.
30. Taton, T.A., G. Lu, and C.A. Mirkin, Two-Color Labeling of Oligonucleotide Arrays via Size-Selective Scattering of Nanoparticle Probes. Journal of the American Chemical Society, 2001. 123: p. 5164-5165.
31. Paciotti, G.F., L. Myer, D. Weinreich, D. Goia, N. Pavel, R.E. McLaughlin, and L. Tamarkin, Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv, 2004. 11: p. 169-183.
32. Oh, N. and J.H. Park, Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomedicine, 2014. 9 p. 51-63.
33. Kruth, H.S., N.L. Jones, W. Huang, B. Zhao, I. Ishii, J. Chang, C. A. Combs, D. Malide, and W.Y. Zhang, Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. The Journal of Biological Chemistry, 2005. 280: p. 2352-2360.
34. Hilgenbrink, A.R. and P.S. Low, Folate receptor-mediated drug targeting: from therapeutics to diagnostics. Journal of Pharmaceutical Sciences, 2005. 94: p. 2135-2146.
35. Yen, H.J., S.H. Hsu, and C.L. Tsai, Cytotoxicity and immunological response of gold and silver nanoparticles of different sizes. Small, 2009. 5: p. 1553-1561.
36. Pan, Y., S. Neuss, A. Leifert, M. Fischler, F. Wen, U. Simon, and G. Schmid, Size-dependent cytotoxicity of gold nanoparticles. Small, 2007. 3: p. 1941-1949.
37. Pan, Y., A. Leifert, D. Ruau, S. Neuss, J. Bornemann, G. Schmid, W. Brandau, U. Simon, and W. Jahnen-Dechent, Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 2009. 5: p. 2067-2076.
38. Tsoli, M., H. Kuhn, W. Brandau, H. Esche, and G. Schmid, Cellular Uptake and Toxicity of Au55 Clusters. Small, 2005. 1: p. 841-844.
39. Pernodet, N.X.F., Y. Sun, A. Bakhtina, A. Ramakrishnan, J. Sokolov, A. Ulman, and M. Rafailovich, Adverse effects of citrate/gold nanoparticles on human dermal fibroblasts. Small, 2006. 2: p. 766-773.
40. Chithrani, B.D., A.A. Ghazani, and W.C.W. Chan, Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells. Nano Letters, 2006. 6: p. 662-668.
41. Gao, H., W. Shi, and L.B. Freund, Mechanics of receptor-mediated endocytosis. Proc Natl Acad Sci U S A, 2005. 102: p. 9469-9474.
42. Cui, W., J. Li, Y. Zhang, and L. Jiang, Effects of aggregation and the surface properties of gold nanoparticles on cytotoxicity and cell growth. Nanomedicine, 2012. 8: p. 46-53.
43. Khlebtsov, N.G. and L.A. Dykman, Optical properties and biomedical applications of plasmonic nanoparticles. Journal of Quantitative Spectroscopy and Radiative Transfer, 2010. 111: p. 1-35.
44. Mu, Q., D.L. Broughton, and B. Yan, Endosomal Leakage and Nuclear Translocation of Multiwalled Carbon Nanotubes: Developing a Model for Cell Uptake. Nano Letters, 2009. 9: p. 4370-4375.
45. Aubin-Tam, M.E. and K. Hamad-Schifferli, Gold Nanoparticle−Cytochrome c Complexes:  The Effect of Nanoparticle Ligand Charge on Protein Structure. Langmuir, 2005. 21: p. 12080-12084.
46. Cho, E.C., J. Xie, P.A. Wurm, and Y. Xia, Understanding the Role of Surface Charges in Cellular Adsorption versus Internalization by Selectively Removing Gold Nanoparticles on the Cell Surface with a I2/KI Etchant. Nano Letters, 2009. 9: p. 1080-1084.
47. Goodman, C.M., C.D. McCusker, T. Yilmaz, and V.M. Rotello, Toxicity of Gold Nanoparticles Functionalized with Cationic and Anionic Side Chains. Bioconjugate Chemistry, 2004. 15: p. 897-900.
48. Hauck, T.S., A.A. Ghazani, and W.C. Chan, Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small, 2008. 4: p. 153-159.
49. Lin, J., H. Zhang, Z. Chen, and Y. Zheng, Penetration of Lipid Membranes by Gold Nanoparticles: Insights into Cellular Uptake, Cytotoxicity, and Their Relationship. ACS Nano, 2010. 4: p. 5421-5429.
50. Connor, E.E., J. Mwamuka, A. Gole, C.J. Murphy, and M.D. Wyatt, Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small, 2005. 1: p. 325-327.
51. Shukla, R., V. Bansal, M. Chaudhary, A. Basu, R.R. Bhonde, and M. Sastry, Biocompatibility of Gold Nanoparticles and Their Endocytotic Fate Inside the Cellular Compartment: A Microscopic Overview. Langmuir, 2005. 21: p. 10644-10654.
52. Lewinski, N., V. Colvin, and R. Drezek, Cytotoxicity of nanoparticles. Small, 2008. 4: p. 26-49.
53. Thomas, M. and A.M. Klibanov, Conjugation to gold nanoparticles enhances polyethylenimine's transfer of plasmid DNA into mammalian cells. Proceedings of the National Academy of Sciences, 2003. 100: p. 9138-9143.
54. Tkachenko, A.G., H. Xie, D. Coleman, W. Glomm, J. Ryan, M.F. Anderson, S. Franzen, and D.L. Feldheim, Multifunctional Gold Nanoparticle−Peptide Complexes for Nuclear Targeting. Journal of the American Chemical Society, 2003. 125: p. 4700-4701.
55. Tkachenko, A.G., H. Xie, Y. Liu, D. Coleman, J. Ryan, W.R. Glomm, M.K. Shipton, S. Franzen, and D.L. Feldheim, Cellular Trajectories of Peptide-Modified Gold Particle Complexes:  Comparison of Nuclear Localization Signals and Peptide Transduction Domains. Bioconjugate Chemistry, 2004. 15: p. 482-490.
56. Fu, W., Shenoy, D.J. Li, C. Crasto, G. Jones, C. Dimarzio, S. Sridhar, and M. Amiji, Biomedical Applications of Gold Nanoparticles Functionalized Using Hetero-Bifunctional Poly(ethylene glycol) Spacer. MRS Online Proceedings Library Archive, 2004. 845: p. 1-6.
57. Murphy, C.J., A.M. Gole, J.W. Stone, P.N. Sisco, E.C. Goldsmith, and S.C. Baxter, Gold Nanoparticles in Biology: Beyond Toxicity to Cellular Imaging. Accounts of Chemical Research, 2008. 41: p. 1721-1730.
58. Liu, D., J.C. Zhang, and C.Q. Yi, The effects of gold nanoparticles on the proliferation, differentiation, and mineralization function of MC3T3-E1 cells in vitro. Chinese Science Bulletin, 2010. 55: p. 1013-1019.
59. Taton, T.A., Nanotechnology: Boning up on biology. Nature, 2001. 412: p. 491-492.
60. Ko, W.K., D.N. Heo, and S.J. Lee, The effect of gold nanoparticle size on osteogenic differentiation of adipose-derived stem cells. Journal of Colloid and Interface Science, 2015. 438: p. 68-76.
61. Brannon-Peppas, L. and J.O. Blanchette, Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev, 2004. 56: p. 1649-1659.
62. Dixit, V., J. Van den Bossche, D.M. Sherman, D.H. Thompson, and R.P. Andres, Synthesis and Grafting of Thioctic Acid−PEG−Folate Conjugates onto Au Nanoparticles for Selective Targeting of Folate Receptor-Positive Tumor Cells. Bioconjugate Chemistry, 2006. 17: p. 603-609.
63. Tong, L., Y. Zhao, T.B. Huff, M.N. Hansen, A. Wei, and J.X. Cheng, Gold Nanorods Mediate Tumor Cell Death by Compromising Membrane Integrity. Advanced Materials, 2007. 19: p. 3136-3141.
64. Cole, J.R., N.A. Mirin, M.W. Knight, G.P. Goodrich, and N.J. Halas, Photothermal Efficiencies of Nanoshells and Nanorods for Clinical Therapeutic Applications. The Journal of Physical Chemistry C, 2009. 113: p. 12090-12094.
65. Han, M.S., A.K. Lytton-Jean, B.K. Oh, J. Heo, and C.A. Mirkin, Colorimetric screening of DNA-binding molecules with gold nanoparticle probes. Angew Chem Int Ed Engl, 2006. 45: p. 1807-1810.
66. Oh, E., M.Y. Hong, D. Lee, S.H. Nam, H.C. Yoon, and H.S. Kim, Inhibition Assay of Biomolecules based on Fluorescence Resonance Energy Transfer (FRET) between Quantum Dots and Gold Nanoparticles. Journal of the American Chemical Society, 2005. 127: p. 3270-3271.
67. Katz , E., W. Itamar,and W. Joseph, Electroanalytical and Bioelectroanalytical Systems Based on Metal and Semiconductor Nanoparticles. Electroanalysis, 2004. 16: p. 19-44.
68. Aroca, R.F., R.A. Alvarez-Puebla, N. Pieczonka, S. Sanchez-Cortez, and J.V. Garcia-Ramos, Surface-enhanced Raman scattering on colloidal nanostructures. Adv Colloid Interface Sci, 2005. 116: p. 45-61.
69. Richard, L.M., Raman Spectroscopy for Chemical Analysis. Measurement Science and Technology, 2001. 12: p. 292-332.
70. Stewart, S., D.A. Shea, C.P. Tarnowski, M.D. Morris, D. Wang, R. Franceschi, D.L. Lin, and E. Keller, Trends in early mineralization of murine calvarial osteoblastic cultures: a Raman microscopic study. Journal of Raman Spectroscopy, 2002. 33: p. 536-543.
71. Hashimoto, A., Y. Yamaguchi, L.D. Chiu, C. Morimoto, K. Fujita, M. Takedachi, S. Kawata, S. Murakami, and E. Tamiya, Time-lapse Raman imaging of osteoblast differentiation. Sci Rep, 2015. 5: p. 12529-12537.
72. Chiang, Y.H., S.H. Wu, Y.C. Kuo, H.F. Chen, A. Chiou, and O.K. Lee, Raman spectroscopy for grading of live osteosarcoma cells. Stem Cell Res Ther, 2015. 6: p. 81-90.
73. Kang, L.L., Y.X. Huang, and Z..J. Wu, Study of Spectrum Processing Method for Raman Microscopy on Single Living cell. Sci Rep, 2011. 31: p. 408-411.
74. Fleischman, M., P. Hendra, and A. McQuillan, Surface-enhanced Raman scattering from silver particles on polymer-replica substrates. Chem Phys Lett, 1974. 26: p. 105-107.
75. Jeanmaire, D.L. and R.P. Van Duyne, Surface Raman spectroelectrochemistry: Part I. Heterocyclic, aromatic, and aliphatic amines adsorbed on the anodized silver electrode. Journal of Electroanalytical Chemistry and Interfacial Electrochemistry, 1977. 84: p. 1-20.
76. Moskovits, M., Surface roughness and the enhanced intensity of Raman scattering by molecules adsorbed on metals. The Journal of Chemical Physics, 2008. 69: p. 4159-4161.
77. Kneipp, K., Y. Wang, H. Kneipp, and I. Itzkan, Population Pumping of Excited Vibrational States by Spontaneous Surface-Enhanced Raman Scattering. Physical Review Letters, 1996. 76: p. 2444-2447.
78. Kneipp, K., H. Kneipp, G. Deinum, I. Itzkan,R.R. Dasari, and M.S. Feld, Single-Molecule Detection of a Cyanine Dye in Silver Colloidal Solution Using Near-Infrared Surface-Enhanced Raman Scattering. Applied Spectroscopy, 1998. 52: p. 175-178.
79. Koglin, E., J. Sequaris, and P. Valenta, Surface Raman spectra of nucleic acid components adsorbed at a silver electrode. Journal of Molecular Structure, 1980. 114: p. 179-194.
80. Cotton, T.M., S.G. Schultz, and R.P. Van Duyne, Surface-enhanced resonance Raman scattering from water-soluble porphyrins adsorbed on a silver electrode. Journal of the American Chemical Society, 1982. 104: p. 6528-6532.
81. Holt, R.E. and T.M. Cotton, Free flavin interference in surface enhanced resonance Raman spectroscopy of glucose oxidase. Journal of the American Chemical Society, 1987. 109: p. 1841-1845.
82. Liu, Z., C. Hu, S. Li, W. Zhang, and Z. Guo, Rapid intracellular growth of gold nanostructures assisted by functionalized graphene oxide and its application for surface-enhanced Raman spectroscopy. Anal Chem, 2012. 84: p. 10338-10344.
83. Hossain, M.K., H. Y. Cho, K. J. Kim, and J. W. Choi, In situ monitoring of doxorubicin release from biohybrid nanoparticles modified with antibody and cell-penetrating peptides in breast cancer cells using surface-enhanced Raman spectroscopy. Biosens Bioelectron, 2015. 71: p. 300-305.
84. Sathuluri, R.R., H. Yoshikawa, E. Shimizu, M. Saito, and E. Tamiya, Gold nanoparticle-based surface-enhanced Raman scattering for noninvasive molecular probing of embryonic stem cell differentiation. PLoS One, 2011. 6: p. 1-13.
85. Katz, E. and I. Willner, Integrated nanoparticle-biomolecule hybrid systems: synthesis, properties, and applications. Angew Chem Int Ed Engl, 2004. 43: p. 6042-6108.
86. Notingher, I., G. Jell, U. Lohbauer, V. Salih, and L.L. Hench, In situ non-invasive spectral discrimination between bone cell phenotypes used in tissue engineering. J Cell Biochem, 2004. 92: p. 1180-1192.
87. McManus, L.L., G.A. Burke, M.M McCafferty, P. O'Hare, M. Modreanu, A.R. Boyd, and B.J. Meenan, Raman spectroscopic monitoring of the osteogenic differentiation of human mesenchymal stem cells. Analyst, 2011. 136: p. 2471-2481.
88. Hashimoto, A., K. Sawada, T. Ikeuchi, K. Fujita, M. Takedachi, Y. Yamaguchi, S. Kawata, S. Murakamib, and E. Tamiyaa, In situ Raman imaging of osteoblastic mineralization. Journal of Raman Spectroscopy, 2014. 45: p. 157-161.
89. Zhang, Y., N. Kohler, and M. Zhang, Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials, 2002. 23: p. 1553-1561.
90. Byrne, J.D., T. Betancourt, and L. Brannon-Peppas, Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev, 2008. 60: p. 1615-1626.
91. The benefits of folic acid-mSamadian, H., S. Hosseini, S.K. Kamrava, H. Ghaznavi, and A. Shakeri-Zadeh, Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy. J Cancer Res Clin Oncol, 2016. 142: p. 2217-2229.
92. Elnakat, H. and M. Ratnam, Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev, 2004. 56: p. 1067-1084.
93. Matherly, L.H., Z. Hou, and Y. Deng, Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev, 2007. 26: p. 111-128.
94. Bharali, D.J., D.W. Lucey, H. Jayakumar, H.E. Pudavar, and P.N. Prasad, Folate-Receptor-Mediated Delivery of InP Quantum Dots for Bioimaging Using Confocal and Two-Photon Microscopy. Journal of the American Chemical Society, 2005. 127: p. 11364-11371.
95. Tsai, S.-W., J.W. Liaw, F.Y. Hsu, Y.Y. Chen, M.J. Lyu, and M.H. Yeh, Surface-Modified Gold Nanoparticles with Folic Acid as Optical Probes for Cellular Imaging. Sensors, 2008. 8: p. 6660-6673.
96. Wang, R., J. Di, J. Ma, and Z. Ma, Highly sensitive detection of cancer cells by electrochemical impedance spectroscopy. Electrochimica Acta, 2012. 61: p. 179-184.
97. Beik, J., M. Jafariyan, A. Montazerabadi, A. Ghadimi, P. Tarighi, A. Mahmoudabadi, H. Ghaznavi, and A. Shakeri, The benefits of folic acid-modified gold nanoparticles in CT-based molecular imaging: radiation dose reduction and image contrast enhancement. Artif Cells Nanomed Biotechnol, 2017. 3: p. 1-9.
98. Sun, C., R. Sze, and M. Zhang, Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. J Biomed Mater Res A, 2006. 78: p. 550-557.
99. Manju, S. and K. Sreenivasan, Gold nanoparticles generated and stabilized by water soluble curcumin-polymer conjugate: blood compatibility evaluation and targeted drug delivery onto cancer cells. Journal of Colloid and Interface Science, 2012. 368: p. 144-151.
100.Du, Y.Q., X.X. Yang, W.L. Li, J. Wang, and C.Z. Huang, A cancer-targeted drug delivery system developed with gold nanoparticle mediated DNA–doxorubicin conjugates. RSC Advances, 2014. 4: p. 34830-34835.
101.Pandey, S., A. Mewada, M. Thakur, R. Shah, G. Oza, and M. Sharon, Biogenic gold nanoparticles as fotillas to fire berberine hydrochloride using folic acid as molecular road map. Mater Sci Eng C Mater Biol Appl, 2013. 33: p. 3716-3722.
102.Zhao, S.S., N. Bukar, J.L. Toulouse, D. Pelechacz, R. Robitaille, J.N. Pelletier, and J.F. Masson, Miniature multi-channel SPR instrument for methotrexate monitoring in clinical samples. Biosens Bioelectron, 2015. 64: p. 664-670.
103.Ladino, C.A., R.V.J. Chari, L.A. Bourret, N.L. Kedersha, and V.S. Goldmacher, Folate-maytansinoids: Target-selective drugs of low molecular weight. International Journal of Cancer, 1997. 73: p. 859-864.
104.Atkinson, S.F., T. Bettinger, L.W. Seymour, J.P. Behr, and C.M. Ward, Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells. J Biol Chem, 2001. 276: p. 27930-27935.
105.Leamon, C.P., M.A. Parker, I.R. Vlahov, L.C. Xu, J.A. Reddy, M. Vetzel, and N. Douglas, Synthesis and Biological Evaluation of EC20:  A New Folate-Derived, 99mTc-Based Radiopharmaceutical. Bioconjugate Chemistry, 2002. 13: p. 1200-1210.
106.John, C., B. Linda, P.M. Edgar, and M. Fernando, Photochemical Synthesis of the Bioconjugate Folic Acid-Gold Nanoparticles. Nanomaterials and Nanotechnology, 2013. 3: p. 1-6.
107.Zhang, Z., J. Jia, Y. Ma, J. Weng, Y. Sun, and L. Sun, Microwave-assisted one-step rapid synthesis of folic acid modified gold nanoparticles for cancer cell targeting and detection. MedChemComm, 2011. 2: p. 1079-1082.
108.Neshastehriz, A., M. Tabei, S. Maleki, S. Eynali, and A. Shakeri, Photothermal therapy using folate conjugated gold nanoparticles enhances the effects of 6MV X-ray on mouth epidermal carcinoma cells. J Photochem Photobiol B, 2017. 172: p. 52-60.
109.Raisz, L.G., Physiology and pathophysiology of bone remodeling. Clinical Chemistry, 1999. 45: p. 1353-1358.
110.Kostura, L., D.L. Kraitchman, A.M. Mackay, M.F. Pittenger, and J.W.M. Bulte, Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR in Biomedicine, 2004. 17: p. 513-517.
111.Andreas, K., R. Georgieva, M. Ladwig, M. Notter, M. Sittinger, and J. Ringe, Highly efficient magnetic stem cell labeling with citrate-coated superparamagnetic iron oxide nanoparticles for MRI tracking. Biomaterials, 2012. 33: p. 4515-4525.
112.Caplan, A.I. and S.P. Bruder, Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends in Molecular Medicine, 2001. 7: p. 259-264.
113.Stein, G.S., J.B. Lian, J.L. Stein, A.J. VanWijnen, and M. Montecino, Transcriptional control of osteoblast growth and differentiation. Physiological Reviews, 1996. 76: p. 593-629.
114.Liu, X., J. Cao, H. Li, J. Li, Q. Jin, K. Ren, and J. Ji Mussel-Inspired Polydopamine: A Biocompatible and Ultrastable Coating for Nanoparticles in Vivo. ACS Nano, 2013. 7: p. 9384–9395
115.Ji, X., X. Song, J. Li, Y. Bai, W. Yang, and X. Peng, Size Control of Gold Nanocrystals in Citrate Reduction The Third Role of Citrate. Journal of the American Chemical Society, 2007. 129: p. 13939-13948.
116.Tyagi, H., A. Kushwaha, A. Kumar, and M. Aslam, A Facile pH Controlled Citrate-Based Reduction Method for Gold Nanoparticle Synthesis at Room Temperature. Nanoscale Res Lett, 2016. 11: p. 362-373.
117.Kim, K.M., H.M. Kim, W.J. Lee, C.W. Lee, T.I. Kim, J.K. Lee, J. Jeong, S.M. Paek, and J. M. Oh, Surface treatment of silica nanoparticles for stable and charge-controlled colloidal silica. Int J Nanomedicine, 2014. 9 p. 29-40.
118.Meiser, F., C. Cortez, and F. Caruso, Biofunctionalization of Fluorescent Rare-Earth-Doped Lanthanum Phosphate Colloidal Nanoparticles. Angewandte Chemie, 2004. 116: p. 6080-6083.
119.Franca, A., B. Pelaz, M. Moros, C. Sanchez, A. Hernandez, V. Grazu, J.M. de la Fuente, I. Pastoriza, L.M. Liz-Marzan, and A. Gonzalez-Fernandez, Sterilization matters: consequences of different sterilization techniques on gold nanoparticles. Small, 2010. 6: p. 89-95.
120.ROSS, K.F.A., and G. GALAVAZIt, The size of bacteria, as measured by interference microscopy. Journal of the Royal microscopical Society banner, 1964. 84: p. 13-25.
121.Raouf, A.L.M., K. Hammud, J. Mahdi, E.M.K. Dulimyi, Qualitative and Quantitative Determination of Folic acid in Tablets by FTIR Spectroscopy. International Journal of advances in Pharmacy, Biology and Chemistry, 2014. 3: p. 773-780.
122.Naraprawatphong, R., G. Kawanaka, M. Hayashi, A. Kawamura, and T. Miyata, Development of protein-recognition SPR devices by combination of SI-ATRP with biomolecular imprinting using protein ligands. Molecular Imprinting, 2016. 4: p. 21-30.
123.Albanese, A. and W.C.W. Chan, Effect of Gold Nanoparticle Aggregation on Cell Uptake and Toxicity. ACS Nano, 2011. 5: p. 5478-5489.
124.Cedervall, T., I. Lynch, M. Foy, T. Berggard, S. C. Donnelly, G. Cagney, S. Linse, and K.A. Dawson, Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew Chem Int Ed Engl, 2007. 46: p. 5754-5756.
125.Absolom, D.R., W. Zingg, and A.W. Neumann, Protein adsorption to polymer particles: role of surface properties. Journal of Biomedical Materials Research, 1987. 21: p. 161-171.
126.Mustafa, T., F. Watanabe, and W. Monroe, Impact of Gold Nanoparticle Concentration on their Cellular Uptake by MC3T3-E1 Mouse Osteoblastic Cells as Analyzed by Transmission Electron Microscopy. Journal of Nanomedicine & Nanotechnology, 2011. 02: p. 1-7.
127.Adams, J.C. and F.M. Watt, Regulation of development and differentiation by the extracellular matrix. Development, 1993. 117: p. 1183-1198.
128.Chen, C.S., M. Mrksich, S. Huang, G.M. Whitesides, and D.E. Ingber, Geometric Control of Cell Life and Death. Science, 1997. 276: p. 1425-1428.
129.Richter, L., V. Charwat, C. Jungreuthmayer, F. Bellutti, H. Brueckl, and P. Ertl, Monitoring cellular stress responses to nanoparticles using a lab-on-a-chip. Lab Chip, 2011. 11: p. 2551-2560.
130.Hanlon, E.B., K.E. Shafer, and J.T. Motz, Prospects for in vivo Raman spectroscopy. Physics in Medicine and Biology, 2000. 45: p. 1-59.
131.Mandair, G.S. and M.D. Morris, Contributions of Raman spectroscopy to the understanding of bone strength. Bonekey Rep, 2015. 4: p. 620-628.
132.Hung, P.S., Y.C. Kuo, H.G. Chen, H.H. Chiang, and O.K. Lee, Detection of osteogenic differentiation by differential mineralized matrix production in mesenchymal stromal cells by Raman spectroscopy. PLoS One, 2013. 8: p. 65438-65445.