Carbon nanotubes as delivery systems for respiratory disease: do the dangers outweigh the potential benefits?

Abstract

Nanoparticle drug-delivery systems offer the potential for improved efficacy of treatment, and yet there are also potential risks associated with these novel therapeutic strategies. An attractive property of carbon nanotubes (CNTs) is that the tube- or fiber-like structure allows for extensive functionalization and loading of cargo. However, a large body of evidence indicates that CNTs may have adverse effects if used in drug delivery as they have been shown to cause pulmonary fibrosis and exacerbate lung disease in rodents with pre-existing lung diseases. Major factors that cause these toxic effects are the high aspect ratio, durability and residual metal content that generate reactive oxygen species. Therefore, careful consideration should be given to the possibility that lung inflammation or fibrosis could be significant side effects caused by a CNT-based drug-delivery system, thereby outweighing any potential beneficial effects of therapeutic treatment. However, functionalization of CNTs to modulate aspect ratio, biodegradability and to remove residual metals could allow for safe design of CNTs for use in drug delivery in certain circumstances.

Figure 1. Hypothetical outcomes of altering the physicochemical properties of carbon nanotubes for drug delivery

Inhaled pristine CNTs aggregate and are taken up by macrophages, where they stimulate ROS generation and activation of the inflammasome to produce IL-1β, a proximal mediator of pulmonary fibrosis. Purifying CNTs to remove residual metal catalysts reduces ROS, macrophage activation and fibrosis. Functionalization of CNTs to increase dispersability and modify biodegradation would be needed for drug delivery and could result in evasion of macrophage uptake and increased bioavailability. Further functionalization could involve attachment of therapeutic agents and allowing for cell-specific targeting. The ultimate success of using CNTs as a drug-delivery platform would depend on the risk of side effects (fibrosis or cancer) in relation to effective therapy of a particular disease. CNT: Carbon nanotube; ROS: Reactive oxygen species.

Figure 2. Postulated susceptibility factors to carbon nanotube exposure and associated pathologic or physiologic consequences

Mouse models of susceptibility have been used to demonstrate that pre-existing inflammation induced by allergens to induce experimental asthma, bacterial wall products or bacterial infection increase lung fibrogenic reactions to CNTs. Factors that influence CNT-induced exacerbation of pre-existing disease include reduced mucociliary clearance of CNTs in asthma or COPD, and enhanced inflammation by CNTs when combined with microbial infection. Susceptibility genes also probably play an important role in determining severity of disease outcome in response to CNTs. CNT: Carbon nanotube; COPD: Chronic obstructive pulmonary disease.