Designing a Nanocargo with Fe3O4@Au: A Tri-pronged Mechanism for MR Imaging, Synaphic Drug-Delivery, and Apoptosis Induction in Cancer Cells

  • Ravichandran Manisekaran
Part of the Springer Theses book series (Springer Theses)


Cancer, considered as a hallmark of diseases, is responsible for second most mortality and morbidity rates. The greatest discovery in the fundamental cancer biology has not been transformed into clinical therapeutics. There is a vast incongruity existing due to lack of translational medicine targeting towards the cancerous cells both temporally and spatially. Moreover, the drugs available possess a plethora of side effects and are incapable of circumventing the biophysical barriers posed by tumor microphysiology. The two nano-vectors, viz., drug-delivery and imaging have come to the rescue in such a debilitating condition of cancer therapeutics.


  1. 1.
    Wilhelm, C., Lavialle, F., Péchoux, C., Tatischeff, I. & Gazeau, F. Intracellular trafficking of magnetic nanoparticles to design multifunctional biovesicles. Small 4, 577–582 (2008).CrossRefGoogle Scholar
  2. 2.
    Cheng, F. Y. et al. Characterization of aqueous dispersions of Fe3O4 nanoparticles and their biomedical applications. Biomaterials 26, 729–738 (2005).CrossRefGoogle Scholar
  3. 3.
    Hergt, R. & Dutz, S. Magnetic particle hyperthermia-biophysical limitations of a visionary tumour therapy. J. Magn. Magn. Mater. 311, 187–192 (2007).CrossRefGoogle Scholar
  4. 4.
    Habib, A. H., Ondeck, C. L., Chaudhary, P., Bockstaller, M. R. & McHenry, M. E. Evaluation of iron-cobalt/ferrite core-shell nanoparticles for cancer thermotherapy. J. Appl. Phys. 103, 07A307 (2008).CrossRefGoogle Scholar
  5. 5.
    Lübbe, A. S. et al. Clinical experiences with magnetic drug targeting: a phase I study with 4′-epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res. 56, 4686–4693 (1996).Google Scholar
  6. 6.
    Alexiou, C. et al. Locoregional cancer treatment with magnetic drug targeting. Cancer Res. 60, 6641–6648 (2000).Google Scholar
  7. 7.
    Widder, K. J., Senyei, A. E. & Scarpelli, D. G. Magnetic Microspheres: A Model System for Site Specific Drug Delivery in Vivo. Exp. Biol. Med. 158, 141–146 (1978).CrossRefGoogle Scholar
  8. 8.
    Maeda, H., Wu, J., Sawa, T., Matsumura, Y. & Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. J. Control. Release 65, 271–284 (2000).CrossRefGoogle Scholar
  9. 9.
    Wang, S. & Low, P. S. Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. J. Control. Release 53, 39–48 (1998).CrossRefGoogle Scholar
  10. 10.
    Wang, Y., Wei, X., Zhang, C., Zhang, F. & Liang, W. Nanoparticle delivery strategies to target doxorubicin to tumor cells and reduce side effects. Ther Deliv 1, 273–287 (2010).CrossRefGoogle Scholar
  11. 11.
    Tang, X. & Pan, C. Y. Double hydrophilic block copolymers PEO-b-PGA: Synthesis, application as potential drug carrier and drug release via pH-sensitive linkage. J. Biomed. Mater. Res. - Part A 86, 428–438 (2008).CrossRefGoogle Scholar
  12. 12.
    Rejinold, N. S., Chennazhi, K. P., Nair, S. V., Tamura, H. & Jayakumar, R. Biodegradable and thermo-sensitive chitosan-g-poly(N-vinylcaprolactam) nanoparticles as a 5-fluorouracil carrier. Carbohydr. Polym. 83, 776–786 (2011).CrossRefGoogle Scholar
  13. 13.
    Glangchai, L. C., Caldorera-Moore, M., Shi, L. & Roy, K. Nanoimprint lithography based fabrication of shape-specific, enzymatically-triggered smart nanoparticles. J. Control. Release 125, 263–272 (2008).CrossRefGoogle Scholar
  14. 14.
    Low, P. S. & Antony, A. C. Folate receptor-targeted drugs for cancer and inflammatory diseases. Adv. Drug Deliv. Rev. 56, 1055–1058 (2004).CrossRefGoogle Scholar
  15. 15.
    Guo, M. et al. Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery. Biomaterials 32, 185–194 (2011).CrossRefGoogle Scholar
  16. 16.
    Sonvico, F. et al. Folate-conjugated iron oxide nanoparticles for solid tumor targeting as potential specific magnetic hyperthermia mediators: Synthesis, physicochemical characterization, and in vitro experiments. Bioconjug. Chem. 16, 1181–1188 (2005).CrossRefGoogle Scholar
  17. 17.
    Wang, Y., Wang, Y., Xiang, J. & Yao, K. Target-specific cellular uptake of taxol-loaded heparin-PEG-folate nanoparticles. Biomacromolecules 11, 3531–3538 (2010).CrossRefGoogle Scholar
  18. 18.
    Sun, C., Sze, R. & Zhang, M. Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. J. Biomed. Mater. Res. - Part A 78, 550–557 (2006).CrossRefGoogle Scholar
  19. 19.
    Cirstoiu-Hapca, A., Bossy-Nobs, L., Buchegger, F., Gurny, R. & Delie, F. Differential tumor cell targeting of anti-HER2 (Herceptin®) and anti-CD20 (Mabthera®) coupled nanoparticles. Int. J. Pharm. 331, 190–196 (2007).CrossRefGoogle Scholar
  20. 20.
    Leuschner, C. et al. LHRH-conjugated magnetic iron oxide nanoparticles for detection of breast cancer metastases. Breast Cancer Res. Treat. 99, 163–176 (2006).CrossRefGoogle Scholar
  21. 21.
    Veiseh, O. et al. Inhibition of tumor-cell invasion with chlorotoxin-bound superparamagnetic nanoparticles. Small 5, 256–264 (2009).CrossRefGoogle Scholar
  22. 22.
    Yigit, M. V., Mazumdar, D. & Lu, Y. MRI detection of thrombin with aptamer functionalized superparamagnetic iron oxide nanoparticles. Bioconjug. Chem. 19, 412–417 (2008).CrossRefGoogle Scholar
  23. 23.
    Peterson, A. W., Wolf, L. K. & Georgiadis, R. M. Hybridization of mismatched or partially matched DNA at surfaces. J. Am. Chem. Soc. 124, 14601–14607 (2002).CrossRefGoogle Scholar
  24. 24.
    Vijayendran, R. A. & Leckband, D. E. A quantitative assessment of heterogeneity for surface-immobilized proteins. Anal. Chem. 73, 471–480 (2001).CrossRefGoogle Scholar
  25. 25.
    Van Dijk, M. A. et al. Absorption and scattering microscopy of single metal nanoparticles. Phys. Chem. Chem. Phys. 8, 3486–95 (2006).CrossRefGoogle Scholar
  26. 26.
    Robinson, I., Tung, L. D., Maenosono, S., Wälti, C. & Thanh, N. T. K. Synthesis of core-shell gold coated magnetic nanoparticles and their interaction with thiolated DNA. Nanoscale 2, 2624–2630 (2010).CrossRefGoogle Scholar
  27. 27.
    Karaagac, O., Kockar, H., Beyaz, S. & Tanrisever, T. A simple way to synthesize superparamagnetic iron oxide nanoparticles in air atmosphere: Iron ion concentration effect. IEEE Trans. Magn. 46, 3978–3983 (2010).CrossRefGoogle Scholar
  28. 28.
    Yu, F., Yao, D. & Knoll, W. Oligonucleotide hybridization studied by a surface plasmon diffraction sensor (SPDS). Nucleic Acids Res. 32, e75 (2004).CrossRefGoogle Scholar
  29. 29.
    Okahata, Y. et al. Kinetic Measurements of DNA Hybridization on an Oligonucleotide-Immobilized 27-MHz Quartz Crystal Microbalance. Anal. Chem. 70, 1288–1296 (1998).CrossRefGoogle Scholar
  30. 30.
    Fan, A., Lau, C. & Lu, J. Magnetic bead-based chemiluminescent metal immunoassay with a colloidal gold label. Anal. Chem. 77, 3238–3242 (2005).CrossRefGoogle Scholar
  31. 31.
    Schroder, L., Lowery, T. J., Hilty, C., Wemmer, D. E. & Pines, A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science . 314, 446 (2006).CrossRefGoogle Scholar
  32. 32.
    Xu, Z., Hou, Y. & Sun, S. Magnetic core/shell Fe3O4/Au and Fe3O4/Au/Ag nanoparticles with tunable plasmonic properties. J. Am. Chem. Soc. 129, 8698–8699 (2007).CrossRefGoogle Scholar
  33. 33.
    Thaxton, C. S., Mirkin, C. A. & Nam, J. Nanoparticle-Based Bio – Bar Codes for the Ultrasensitive Detection of Proteins. Science. 301, 1884–1886 (2003).CrossRefGoogle Scholar
  34. 34.
    Aslan, K., Lakowicz, J. R. & Geddes, C. D. Plasmon light scattering in biology and medicine: New sensing approaches, visions and perspectives. Curr. Opin. Chem. Biol. 9, 538–544 (2005).CrossRefGoogle Scholar
  35. 35.
    Thanh, N. T. K. & Green, L. A. W. Functionalisation of nanoparticles for biomedical applications. Nano Today 5, 213–230 (2010).CrossRefGoogle Scholar
  36. 36.
    Huang, C., Jiang, J., Muangphat, C., Sun, X. & Hao, Y. Trapping Iron Oxide into Hollow Gold Nanoparticles. Nanoscale Res. Lett. 6, 1–5 (2011).CrossRefGoogle Scholar
  37. 37.
    Tiller, W. A. The Science of Crystallization. (Cambridge University Press, 1991). doi:
  38. 38.
    Rao, C. N. R., Müller, A. & Cheetham, A. K. Nanomaterials Chemistry: Recent Developments and New Directions. Nanomaterials Chemistry: Recent Developments and New Directions (Wiley-VCH Verlag GmbH & Co. KGaA, 2007). doi:
  39. 39.
    Luzar, A. & Chandler, D. Structure and hydrogen bond dynamics of water–dimethyl sulfoxide mixtures by computer simulations. J. Chem. Phys. 98, 8160–8173 (1993).CrossRefGoogle Scholar
  40. 40.
    Murphy, C. J. et al. The many faces of gold nanorods. J. Phys. Chem. Lett. 1, 2867–2875 (2010).CrossRefGoogle Scholar
  41. 41.
    Goon, I. Y. et al. Fabrication and dispersion of gold-shell-protected magnetite nanoparticles: Systematic control using polyethyleneimine. Chem. Mater. 21, 673–681 (2009).CrossRefGoogle Scholar
  42. 42.
    Barr, T. L. An ESCA study of the termination of the passivation of elemental metals. J. Phys. Chem. 82, 1801–1810 (1978).CrossRefGoogle Scholar
  43. 43.
    Wang, F. Quantitative Methods and Applications in GIS. (CRC Press, 2006). doi:
  44. 44.
    Jaramillo, T. F., Baeck, S. H., Cuenya, B. R. & McFarland, E. W. Catalytic activity of supported Au nanoparticles deposited from block copolymer micelles. J. Am. Chem. Soc. 125, 7148–7149 (2003).CrossRefGoogle Scholar
  45. 45.
    Lo, C. K. et al. Homocysteine-protected gold-coated magnetic nanoparticles: synthesis and characterisation. J. Mater. Chem. 17, 2418 (2007).CrossRefGoogle Scholar
  46. 46.
    Siegbahn, K. Electron Spectroscopy for Chemical Analysis (E.S.C.A.). Philos. Trans. R. Soc. London A Math. Phys. Eng. Sci. 268, (1970).Google Scholar
  47. 47.
    Liu, H., Jiang, E. Y., Zheng, R. K. & Bai, H. L. Structure and magnetic properties of polycrystalline Fe3O4 films deposited by reactive sputtering at room temperature. Phys. Status Solidi 201, 739–744 (2004).CrossRefGoogle Scholar
  48. 48.
    Vogelson, C. T. et al. Molecular coupling layers formed by reactions of epoxy resins with self-assembled carboxylate monolayers grown on the native oxide of aluminium. J. Mater. Chem. 13, 291–296 (2003).CrossRefGoogle Scholar
  49. 49.
    Mohapatra, S. & Pramanik, P. Synthesis and stability of functionalized iron oxide nanoparticles using organophosphorus coupling agents. Colloids Surfaces A Physicochem. Eng. Asp. 339, 35–42 (2009).CrossRefGoogle Scholar
  50. 50.
    Řıhová, B. Receptor-mediated targeted drug or toxin delivery. Adv. Drug Deliv. Rev. 29, 273–289 (1998).Google Scholar
  51. 51.
    Swaan, P. W. Recent Advances in Intestinal Macromolecular Drug Delivery via Receptor-Mediated Transport Pathways. Pharm. Res. 15, 826–834 (1998).CrossRefGoogle Scholar
  52. 52.
    Cezar, G. G. et al. Identification of small molecules from human embryonic stem cells using metabolomics. Stem Cells Dev. 16, 869–882 (2007).CrossRefGoogle Scholar
  53. 53.
    Weitman, S. D. et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 52, 3396–401 (1992).Google Scholar
  54. 54.
    Ross, J. F., Chaudhuri, P. K. & Ratnam, M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73, 2432–43 (1994).CrossRefGoogle Scholar
  55. 55.
    Gabizon, A. et al. Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: In vitro studies. Bioconjug. Chem. 10, 289–298 (1999).CrossRefGoogle Scholar
  56. 56.
    Lu, Y. & Low, P. S. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv. Drug Deliv. Rev. 54, 675–693 (2002).CrossRefGoogle Scholar
  57. 57.
    Stella, B. et al. Design of folic acid-conjugated nanoparticles for drug targeting. J. Pharm. Sci. 89, 1452–1464 (2000).CrossRefGoogle Scholar
  58. 58.
    Dántola, M. L. et al. Mechanism of photooxidation of folic acid sensitized by unconjugated pterins. Photochem. Photobiol. Sci. 9, 1604–1612 (2010).CrossRefGoogle Scholar
  59. 59.
    Chen, X., Tang, Y., Cai, B. & Fan, H. ‘One-pot’ synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery. Nanotechnology 25, 235101 (2014).CrossRefGoogle Scholar
  60. 60.
    Ravichandran, M. et al. Plasmonic/Magnetic Multifunctional nanoplatform for Cancer Theranostics. Sci. Rep. 6, 34874 (2016).CrossRefGoogle Scholar
  61. 61.
    Honary, S., Barabadi, H., Gharaei-Fathabad, E. & Naghibi, F. Green Synthesis of Silver Nanoparticles Induced by the Fungus Penicillium citrinum. Trop. J. Pharm. Res. 12, 7–11 (2013).Google Scholar
  62. 62.
    Ede, S. R., Nithiyanantham, U. & Kundu, S. Enhanced catalytic and SERS activities of CTAB stabilized interconnected osmium nanoclusters. Phys. Chem. Chem. Phys. 16, 22723–22734 (2014).CrossRefGoogle Scholar
  63. 63.
    Zhang, J., Rana, S., Srivastava, R. S. & Misra, R. D. K. On the chemical synthesis and drug delivery response of folate receptor-activated, polyethylene glycol-functionalized magnetite nanoparticles. Acta Biomater. 4, 40–48 (2008).CrossRefGoogle Scholar
  64. 64.
    Yuan, Q., Hein, S. & Misra, R. D. K. New generation of chitosan-encapsulated ZnO quantum dots loaded with drug: Synthesis, characterization and in vitro drug delivery response. Acta Biomater. 6, 2732–2739 (2010).CrossRefGoogle Scholar
  65. 65.
    Pandey, S. et al. Folic acid mediated synaphic delivery of doxorubicin using biogenic gold nanoparticles anchored to biological linkers. J. Mater. Chem. B 1, 1361 (2013).CrossRefGoogle Scholar
  66. 66.
    Huang, J., Su, P., Zhao, B. & Yang, Y. Facile one-pot synthesis of β-cyclodextrin-polymer-modified Fe3O4 microspheres for stereoselective absorption of amino acid compounds. Anal. Methods 7, 2754–2761 (2015).CrossRefGoogle Scholar
  67. 67.
    Chen, J., Wang, Y., Ding, X., Huang, Y. & Xu, K. Analytical Methods on hydroxy functional ionic liquid-modi fi ed magnetic nanoparticles. Anal. Methods 6, 8358–8367 (2014).CrossRefGoogle Scholar
  68. 68.
    Sanders, J. P. & Gallagher, P. K. Thermomagnetometric evidence of γ-Fe2O3 as an intermediate in the oxidation of magnetite. Thermochim. Acta 406, 241–243 (2003).CrossRefGoogle Scholar
  69. 69.
    Rai, A., Prabhune, A. & Perry, C. C. Antibiotic mediated synthesis of gold nanoparticles with potent antimicrobial activity and their application in antimicrobial coatings. J. Mater. Chem. 20, 6789 (2010).CrossRefGoogle Scholar
  70. 70.
    Basavegowda, N., Idhayadhulla, A. & Lee, Y. R. Phyto-synthesis of gold nanoparticles using fruit extract of Hovenia dulcis and their biological activities. Ind. Crops Prod. 52, 745–751 (2014).CrossRefGoogle Scholar
  71. 71.
    Sahoo, B. et al. Facile preparation of multifunctional hollow silica nanoparticles and their cancer specific targeting effect. Biomater. Sci. 1, 647 (2013).CrossRefGoogle Scholar
  72. 72.
    Jin, H. et al. Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo. Sci. Rep. 6, 30782 (2016).CrossRefGoogle Scholar
  73. 73.
    Shenderova, O., Hens, S. & McGuire, G. Seeding slurries based on detonation nanodiamond in DMSO. Diam. Relat. Mater. 19, 260–267 (2010).CrossRefGoogle Scholar
  74. 74.
    Zhang, W., Patel, K., Schexnider, A., Banu, S. & Radadia, A. D. Nanostructuring of biosensing electrodes with nanodiamonds for antibody immobilization. ACS Nano 8, 1419–28 (2014).CrossRefGoogle Scholar
  75. 75.
    Wang, L. et al. Surface chemistry of gold nanorods: origin of cell membrane damage and cytotoxicity. Nanoscale 5, 8384 (2013).CrossRefGoogle Scholar
  76. 76.
    Ricles, L. M., Nam, S. Y., Treviño, E. A., Emelianov, S. Y. & Suggs, L. J. A dual gold nanoparticle system for mesenchymal stem cell tracking. J. Mater. Chem. B 2, 8220–8230 (2014).CrossRefGoogle Scholar
  77. 77.
    Das, M., Mishra, D., Maiti, T. K., Basak, A & Pramanik, P. Bio-functionalization of magnetite nanoparticles using an aminophosphonic acid coupling agent: new, ultradispersed, iron-oxide folate nanoconjugates for cancer-specific targeting. Nanotechnology 19, 415101 (2008).CrossRefGoogle Scholar
  78. 78.
    Pandey, S. et al. Carbon dots functionalized gold nanorod mediated delivery of doxorubicin: tri-functional nano-worms for drug delivery, photothermal therapy and bioimaging. J. Mater. Chem. B 1, 4972 (2013).CrossRefGoogle Scholar
  79. 79.
    Kamen, B. A. & Capdevila, A. Receptor-mediated folate accumulation is regulated by the cellular folate content (5-methyltetrahydro[3H]folate binding/folate-binding factor). Cell Biol. 83, 5983–5987 (1986).Google Scholar
  80. 80.
    Leamon, C. P. & Low, P. S. Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. Proc. Natl. Acad. Sci. U. S. A. 88, 5572–6 (1991).CrossRefGoogle Scholar
  81. 81.
    Estrella, V. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73, 1524–1535 (2013).CrossRefGoogle Scholar
  82. 82.
    Rybak, S. L. & Murphy, R. F. Primary cell cultures from murine kidney and heart differ in endosomal pH. J. Cell. Physiol. 176, 216–222 (1998).CrossRefGoogle Scholar
  83. 83.
    Scherzinger, A. L. & Hendee, W. R. Basic principles of magnetic resonance imaging--an update. West. J. Med. 143, 782–92 (1985).Google Scholar
  84. 84.
    Pooley, R. A. Fundamental Physics of MR ImagingRadioGraphics 25, 1087–1099 (2005).CrossRefGoogle Scholar
  85. 85.
    Krishnan, K. M. Advances in Magnetics Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy. 46, 2523–2558 (2010).Google Scholar
  86. 86.
    B. D. Cullity, C. D. G., Cullity, B. D. & Graham, C. D. Introduction to magnetic materials. 550 (2011).Google Scholar
  87. 87.
    Néel, L. Théorie du traînage magnétique des substances massives dans le domaine de Rayleigh. J. Phys. le Radium 11, 49–61 (1950).CrossRefGoogle Scholar
  88. 88.
    Bettaieb, A. & Averill-Bates, D. A. Thermotolerance induced at a fever temperature of 40 degrees C protects cells against hyperthermia-induced apoptosis mediated by death receptor signalling. Biochem. Cell Biol. 86, 521–538 (2008).CrossRefGoogle Scholar
  89. 89.
    Meenach, S. A., Hilt, J. Z. & Anderson, K. W. Poly(ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy. Acta Biomater. 6, 1039–1046 (2010).CrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  • Ravichandran Manisekaran
    • 1
  1. 1.Center for Research and Advanced Studies of the National Polytechnic InstituteMexico CityMexico

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