Review ArticleToxicity issues in the application of carbon nanotubes to biological systems
Section snippets
Modifying CNTs for use in medicine
As CNTs are intrinsically not water soluble, modification through chemical functionalization using suitable dispersants and surfactants can enhance solubility to the range of g/mL4 and is essential for their controlled dispersion. For example, constituent polar molecules can render CNTs soluble, whereas nonpolar moieties make CNTs immiscible. Such processes have proved especially important in that nonsolubilized CNTs have been found to cause cell death in culture.17, 18, 19
Additionally, the
Toxicity at the level of fabrication and functionalization
Each CNT could be intrinsically different due to limitations on the fabrication of structurally identical CNTs with minimal impurities.33 Subtle variations in local and overall charge, catalyst residue (typically Fe, Co, and Ni), and length of individual nanotubes are three representative issues that preclude precise use of CNTs in the biomedical sciences.
Mechanisms of interaction
Although much progress has been made in understanding how CNTs traverse the lipid membrane of a given cell type, the details of the proposed mechanisms are still debated. Such considerations are important in that the failure to understand the uptake mechanisms of nanoscale materials and their influence on toxicity could create another level of unpredictability.45 To date, two major mechanisms have been widely considered: (1) endocytosis/phagocytosis56 and (2) nanopenetration (Figure 3).
In vitro toxicity: Dosage, tolerance, and regeneration
As with most biomedical research, in vitro tests for toxicity pave the way for future applications in vivo. However, for CNT application, it seems that in vivo studies have been attempted while many questions from in vitro studies have been left unanswered (eg, issues on overall safe CNT dosage for a particular task and the sensitivity of particular cell lines). The probing of such issues is relevant as there may not be a linear relationship between mass and toxicity tolerance.
In vivo toxicity: new insights
Currently, insights into how CNTs behave in the human body (Figure 4) are obtained through recent studies of systemic toxicity, as representatively illustrated in Table 2. To date, the number of studies suggesting CNTs to be nontoxic in vivo outnumbers those proposing otherwise. For example, doses of 20 μg diethylene triamine pentaacetic acid (DTPA)-MWCNT/μL phosphate buffer saline (PBS) and 20 μg DTPA-SWCNT/μL PBS were administered in different mice intravenously with no acute toxicity
Pharmacokinetic profile
The map of CNT pharmacokinetics and biodistribution seems to be developing rapidly. The majority of intravenously injected CNTs in mice mainly seem to be emptied in the urine, with far less found in the liver, spleen, and lungs.74 However, other studies indicate the liver and spleen to be the main sites of CNT accumulation.79 Studies have also found CNT deposits mostly in the excretory systems like the bladder, kidneys, and intestines, in feces,81 and again in the kidneys.69 A contributing
Testing protocol: An unforeseen obstacle
The crux of the experimental method is the process of testing, but what implications will it have on our current understanding of CNT toxicity if some results could arise from internally invalid tests? The argument for increasing testing confidence stems from an in vitro study83 where it was revealed that common amino acids and vitamins (eg, phenylalanine and folate) passively adsorb onto CNTs. Concentrations of SWCNTs as low as 0.01 to 0.1 mg/mL culture was able to deplete 2 nM of folic acid
Conclusions
CNTs have been proposed for use in medicine chiefly for (1) their ability to be functionalized, both covalently and noncovalently, with various moieties, and (2) their aspect ratio and geometry, which enables penetration into the cell. In our survey of existing work and methods, we have found that considerably more fundamental and applied research must be carried out before the viability of CNTs can be realized. One of the major issues affecting nanotube biomedical application is that of charge
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The authors gratefully acknowledge financial support from the National Science Foundation (grant no. ECS-05-08514) and from the Office of Naval Research (award no. N00014-06-1-0234).