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Figure 1. (A.) Artist's cross-sectional image of a carbon nanotube. Image: Digital Art/Corbis. (B.) 3-D renderings of carbon nanotubes of variable diameters and lengths. Image: Joel Brehm, Office of Research and Economic Development, University of Nebraska-Lincoln.

...that the toxicology of carbon nanotubes (CNTs) is hindering their use in the treatment of lung diseases?

Since the discovery of CNTs in 1991 by Sumio Iijima [1], these nanoscaled carbon sheets rolled into hollow tubes and capped at both ends, have caught the attention of biomedical scientists (Figure 1).  However, CNTs are hydrophobic and insoluble in aqueous solution, and tend to aggregate due to strong van der Waals interactions [2].  In order to make CNTs more compatible with biological systems, the insolubility and aggregation issues have been overcome by the attachment of functional groups to the external surface of CNTs in a process known as functionalization [3].  Indeed, in 2001, Chen et al. [4] functionalized CNTs with molecules containing reactive side-chains extending from their surface.  These reactive side-chains were then modified to bind proteins.  In 2004, Pantarotto et al. demonstrated that functionalized CNTs (f-CNTs), modified with a fluorescent probe, readily permeate plasma membranes [5].  Thus, the synthesis of f-CNTs enables the simultaneous immobilization of small biomolecules (e.g. imaging sensors to track delivery) and biomarkers (e.g. antibodies) in addition to drugs or nucleotides thereby enabling selective targeting of CNTs with their associated cargo to certain molecules or cells.  Thus, f-CNTs are promising tools as targeted drug carriers to treat a wide variety of diseases, including diseases of the lungs.

Despite the promise of f-CNTs in drug delivery, studies investigating health risks associated with worker-exposure during the manufacturing process revealed lung toxicity from both inhalation and intravenous delivery routes.  In 2004, rodent studies demonstrated that intratracheal instillation of CNTs produced inflammation and led to the formation of granulomas [6, 7], which became progressively worse with increasing CNT dose [9].  Toxicity was not only attributed to CNT aggregation, but also due to their biopersistence [8, 9].  In 2009, Ryman-Rasmussen demonstrated that inhalation of aerosolized CNT led to subpleural fibrosis in mice but noted the pathology was different from asbestos-associated fibrosis [10].  Intravenous delivery of CNTs in mice induced low toxicity in the liver, spleen and lungs mediated by oxidative stress [11].  In the lungs, an inflammatory response was observed and CNTs aggregates accumulated in the capillaries.  Despite the associated inflammatory risks, CNTs have shown therapeutic promise in a human lung carcinoma animal model, where direct intratumoral delivery of f-CNTs carrying siRNA sequences promoted cell death, reduced tumor volume, increased tumor necrosis, and prolongs animal survival [12].

Though the negative findings are a setback for the use of CNTs as targeted drug carriers to the lung, researchers remain cautiously optimistic.  Functionalization is the key to CNTs as a safe drug delivery system.  CNTs can be modified to make them more dispersable and discourage aggregation.  We now appreciate that while long, thin CNTs behave like asbestos, short or curly CNTs do not [13], suggesting safer CNTs can be made.  Indeed, CNTs of variable diameter and length can now be synthesized (Figure 1B).  CNTs could also be functionalized to render them more biodegradable, so that they do not persist in the lung for an extended period of time [14].  In summary, the current toxicological profile of CNTs in the lung hinders their use as targeted drug carriers to the lung.  However, functionalization of CNTs to reduce aggregation and promote biodegradability as well as altering the aspect ratio of CNTs could decrease lung toxicity.  The technology of targeting drugs to the specific site of disease must be further explored in order to reduce undesirable wide-range systemic effects of a drug and facilitate targeting to the pulmonary circulation.

References 

  1. Iijima, S. (1991) Helical microtubules of graphitic carbon. Nature 354, 56-58
  2. Thess, A., Lee, R., Nikolaev, P., Dai, H., Petit, P., Robert, J., Xu, C., Lee, Y. H., Kim, S. G., Rinzler, A. G., Colbert, D. T., Scuseria, G. E., Tománek, D., Fischer, J. E., and Smalley, R. E. (1996) Crystalline Ropes of Metallic Carbon Nanotubes. Science 273, 483-487
  3. Wang, Y., Iqbal, Z., and Mitra, S. (2005) Rapidly Functionalized, Water-Dispersed Carbon Nanotubes at High Concentration. Journal of the American Chemical Society 128, 95-99
  4. Chen, R. J., Zhang, Y., Wang, D., and Dai, H. (2001) Noncovalent Sidewall Functionalization of Single-Walled Carbon Nanotubes for Protein Immobilization. Journal of the American Chemical Society 123, 3838-3839
  5. Pantarotto, D., Singh, R., McCarthy, D., Erhardt, M., Briand, J.-P., Prato, M., Kostarelos, K., and Bianco, A. (2004) Functionalized Carbon Nanotubes for Plasmid DNA Gene Delivery. Angewandte Chemie International Edition 43, 5242-5246
  6. Warheit, D. B., Laurence, B. R., Reed, K. L., Roach, D. H., Reynolds, G. A. M., and Webb, T. R. (2004) Comparative Pulmonary Toxicity Assessment of Single-wall Carbon Nanotubes in Rats. Toxicological Sciences 77, 117-125
  7. Lam, C.-W., James, J. T., McCluskey, R., and Hunter, R. L. (2004) Pulmonary Toxicity of Single-Wall Carbon Nanotubes in Mice 7 and 90 Days After Intratracheal Instillation. Toxicological Sciences 77, 126-134
  8. Muller, J., Huaux, F., Moreau, N., Misson, P., Heilier, J.-F., Delos, M., Arras, M., Fonseca, A., Nagy, J. B., and Lison, D. (2005) Respiratory toxicity of multi-wall carbon nanotubes. Toxicology and Applied Pharmacology 207, 221-231
  9. Shvedova, A. A., Kisin, E. R., Mercer, R., Murray, A. R., Johnson, V. J., Potapovich, A. I., Tyurina, Y. Y., Gorelik, O., Arepalli, S., Schwegler-Berry, D., Hubbs, A. F., Antonini, J., Evans, D. E., Ku, B.-K., Ramsey, D., Maynard, A., Kagan, V. E., Castranova, V., and Baron, P. (2005) Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. American Journal of Physiology - Lung Cellular and Molecular Physiology 289, L698-L708
  10. Ryman-Rasmussen, J. P., Cesta, M. F., Brody, A. R., Shipley-Phillips, J. K., Everitt, J. I., Tewksbury, E. W., Moss, O. R., Wong, B. A., Dodd, D. E., Andersen, M. E., and Bonner, J. C. (2009) Inhaled carbon nanotubes reach the subpleural tissue in mice. Nature Nanotechnology 4, 747-751
  11. Yang, S.-T., Wang, X., Jia, G., Gu, Y., Wang, T., Nie, H., Ge, C., Wang, H., and Liu, Y. (2008) Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice. Toxicology Letters 181, 182-189
  12. Podesta, J. E., Al-Jamal, K. T., Herrero, M. A., Tian, B., Ali-Boucetta, H., Hegde, V., Bianco, A., Prato, M., and Kostarelos, K. (2009) Antitumor Activity and Prolonged Survival by Carbon-Nanotube-Mediated Therapeutic siRNA Silencing in a Human Lung Xenograft Model. Small 5, 1176-1185
  13. Poland, C. A., Duffin, R., Kinloch, I., Maynard, A., Wallace, W. A. H., Seaton, A., Stone, V., Brown, S., MacNee, W., and Donaldson, K. (2008) Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nature Nanotechnology 3, 423-428
  14. Bianco, A., Kostarelos, K., and Prato, M. (2011) Making carbon nanotubes biocompatible and biodegradable. Chemical Communications 47, 10182-10188

Author: Patricia Villalta
Chief editor: Sarah Sayner, Ph.D., July, 2012

 

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