Colloidal Gold: A Novel Nanoparticle for Targeted Cancer Therapeutics

Part of the Methods in Molecular Biology book series (MIMB, volume 624)


Since their initial description in 1857, gold nanoparticles have been used extensively in the fields of diagnostics and therapeutics. Now, gold nanoparticles are engineered to target the delivery of potent anti-cancer therapeutics to solid tumors to improve either their safety or efficacy or both. Described in this chapter is the development of one such nanotherapeutic, termed CYT-6091, that targets the delivery of tumor necrosis factor alpha (TNF) to solid tumors. Outlined in the presentation is a discussion of nanoparticles and specifically colloidal gold, an historical review on the biology of TNF and its limited use in the clinic when administered systemically, and finally, how gold nanoparticles bound with TNF may improve the safety and efficacy profiles of TNF.

Key words

Tumor necrosis factor colloidal gold colloidal gold nanoparticles pegylated colloidal gold tumor necrosis factor conjugated to colloidal gold 


  1. 1.
    Ferrari, M. (2005) Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 5(3), 161–171.CrossRefPubMedGoogle Scholar
  2. 2.
    Sinha, R., Kim, G. J., Nie, S., and Shin, D. M. (2006) Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol Cancer Ther 5(8), 1909–1917.CrossRefPubMedGoogle Scholar
  3. 3.
    Nie, S., Xing, Y., Kim, G. J., and Simons, J. W. (2007) Nanotechnology applications in cancer. Annu Rev Biomed Eng 9, 257–288.CrossRefPubMedGoogle Scholar
  4. 4.
    Carmeliet, P. and Jain, R. K. (2000) Angiogenesis in cancer and other diseases. Nature 407(6801), 249–257.CrossRefPubMedGoogle Scholar
  5. 5.
    Nagayasu, A., Uchuyama, K., and Kiwada, H. (1999) The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Deliv Rev 40(1–2), 75–87.CrossRefPubMedGoogle Scholar
  6. 6.
    Klibanov, A. L., Maruyama, K., Beckerleg, A. M., Torchilin, V. P., and Huang, L. (1991) Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta 1062(2), 142–148.CrossRefPubMedGoogle Scholar
  7. 7.
    Park, J. W. (2002) Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res 4(3), 95–99.CrossRefPubMedGoogle Scholar
  8. 8.
    Paciotti, G. F., Myer, L., Weinrich, D., et al. (2004) Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv 11(3), 169–183.CrossRefPubMedGoogle Scholar
  9. 9.
    Farma, J., Puhlmann, M., Soriano, P. A., et al. (2007) Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor. Int J Cancer 120(11), 2474–2480.CrossRefPubMedGoogle Scholar
  10. 10.
    Faraday, M. (1857) Experimental relations of gold (and other metals) to light. Philos Trans R Soc Lond B Biol Sci 14, 145–181.Google Scholar
  11. 11.
    Gottlieb, N. L. and Gray, R. G. (1981) Pharmacokinetics of gold in rheumatoid arthritis. Agents Actions Suppl 8, 529–538.PubMedGoogle Scholar
  12. 12.
    Rubin, P. and Levitt, S. H. (1964) The response of disseminated reticulum cell sarcoma to the intravenous injection of colloidal radioactive gold. J Nucl Med 5, 581–594.PubMedGoogle Scholar
  13. 13.
    Root, S. W., Andrews, G. A., Kniseley, R. M., and Tyor, M. P. (1954) The distribution and radiation effects of intravenously administered colloidal Au198 in man. Cancer 7(5), 856–866.CrossRefPubMedGoogle Scholar
  14. 14.
    Holbrook, M. A., Welch, J. S., and Childs, D. S. (1964) Adjuvant use of radioactive colloids in the treatment of carcinoma of the ovary. Radiology 83, 888–891.PubMedGoogle Scholar
  15. 15.
    Fountain, K. S. and Malkasian, G. D. (1981) Radioactive colloidal gold in the treatment of endometrial cancer. Cancer 47, 2430–2432.CrossRefPubMedGoogle Scholar
  16. 16.
    Renaud, G., Hamilton, R. L., and Havel, R. J. (1989) Hepatic metabolism of colloidal gold-low-density-lipoprotein complexes in the rat: evidence for bulk excretion of lysosomal contents into bile. Hepatology 9(3), 380–392.CrossRefPubMedGoogle Scholar
  17. 17.
    Hardonk, M. J., Harms, G., and Koudstaal, J. (1985) Zonal heterogeneity of rat hepatocytes in the in vivo uptake of 17 nm colloidal gold granules. Histochem 83, 473–477.CrossRefGoogle Scholar
  18. 18.
    Carswell, E. A., Old, L. J., Kassel, R. L., et al. (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72(9), 3666–3670.CrossRefPubMedGoogle Scholar
  19. 19.
    Selby, P., Hobbs, S., Jackson, E., et al. (1987) Tumour necrosis factor in man: Clinical and biological observations. Br J Cancer 56(6), 803–808.PubMedGoogle Scholar
  20. 20.
    Pennica, D., Nedwin, G. E., Hayflick, J. S., et al. (1984) Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312(5996), 724–729.CrossRefPubMedGoogle Scholar
  21. 21.
    Chen, G. and Goeddel, D. V. (2002) TNF-RI signaling: a beautiful pathway. Science 296(5573), 1634–5.CrossRefGoogle Scholar
  22. 22.
    Frei, E., 3rd and Spriggs, D. (1989) Tumour necrosis factor: still a promising agent. J Clin Oncol 7(3), 291–294.PubMedGoogle Scholar
  23. 23.
    Chapman, P. B., Lester, T. J., Casper, E. S., et al. (1987) Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer. J Clin Oncol 5(12), 1942–1951.PubMedGoogle Scholar
  24. 24.
    Jakubowski, A. A., Casper, E. S., Gabrilove, J. L., et al. (1989) Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer. J Clin Oncol 7(3), 298–303.PubMedGoogle Scholar
  25. 25.
    Gamm, H., Lindemann, A., Mertelsmann, R., and Herrmann, F. (1991) Phase I trial of recombinant human tumour necrosis factor alpha in patients with advanced malignancy. Eur J Cancer 27(7), 856–863.CrossRefPubMedGoogle Scholar
  26. 26.
    Creaven, P. J., Plager, J. E., Dupere, S., et al. (1987) Phase I Clinical Trial of recombinant human tumor necrosis factor. Cancer Chemother Pharmacol 20(2), 137–144.PubMedGoogle Scholar
  27. 27.
    Taguchi, T. (1988) Phase I study of recombinant human tumor necrosis factor (rHu-TNF:PT-050). Cancer Detect Prev 12(1–6), 561–572.PubMedGoogle Scholar
  28. 28.
    Kemeny, N., Childs, B., Larchian, W., et al. (1990) A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma. Cancer 66(4), 659–663.CrossRefPubMedGoogle Scholar
  29. 29.
    Lenk, H., Tanneberger, S., Muller, U., et al. (1989) Phase II clinical trial of high-dose recombinant human tumor necrosis factor. Cancer Chemother Pharmacol 24(6), 391–2.CrossRefGoogle Scholar
  30. 30.
    Feldman, E. R., Creagan, E. T., Schaid, D. J., and Ahmann, D. L. (1992) Phase II trial of recombinant tumor necrosis factor in disseminated malignant melanoma. Am J Clin Oncol 15(3), 256–259.CrossRefPubMedGoogle Scholar
  31. 31.
    Budd, G. T., Green, S., Baker, L. H., et al. (1991) A southwest oncology group phase ii trial of recombinant tumor necrosis factor in metastatic breast cancer. Cancer 68(8), 1694–5.CrossRefGoogle Scholar
  32. 32.
    Haranaka, K., Satomi, N., and Sakurai, A. (1984) Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int J Cancer 34(2), 263–267.CrossRefPubMedGoogle Scholar
  33. 33.
    Lienard, D., Ewalenko, P., Delmotte, J. J., et al. (1992) High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 10(1), 52–60.PubMedGoogle Scholar
  34. 34.
    Fraker, D. L., Alexander, H. R., Andrich, M., and Rosenberg, S. A. (1996) Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 14(2), 479–489.PubMedGoogle Scholar
  35. 35.
    Dvorak, A. M., Kohn, S., Morgan, E. S., et al. (1996) The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J Leukoc Biol 59(1), 100–115.PubMedGoogle Scholar
  36. 36.
    Feng, D., Nagy, J., Hipp, J., et al. (1996) Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 183(5), 1981–1986.CrossRefPubMedGoogle Scholar
  37. 37.
    Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., and McDonald, D. M. (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4), 1363–1380.PubMedGoogle Scholar
  38. 38.
    Jain, R. K. (2003) Molecular regulation of vessel maturation. Nat Med 9(6), 685–693.CrossRefPubMedGoogle Scholar
  39. 39.
    Folkman, J. (1971) Tumor angiogenesis: therapeutic implications. New Engl J Med 285(21), 1182–1186.CrossRefPubMedGoogle Scholar
  40. 40.
    Hermanson, G. T. (1996) Preparation of colloidal-gold labeled proteins. in Bioconjugate Techniques. Academic Press, Inc., San Diego, pp. 594–597.Google Scholar
  41. 41.
    Libutti, S. K., Paciotti, G. F., Myer, L., et al. Preliminary results of a phase I clinical trial of CYT-6091: A pegylated colloidal-gold TNF. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings, Part I. Vol 25, No. 18S (June 20 Supplement), 3603.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Tumor Angiogenesis Section, Surgery BranchNational Cancer InstituteBethesdaUSA
  2. 2.CytImmune Sciences, Inc.RockvilleUSA

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