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[email protected] Potential uses of carbon nanotubes in the
medical field: how worried should patients be?
‘…the same novel properties that
make CNTs interesting raise
concerns about their potential
adverse effects on biological
systems, which could lead to
health issues, particularly when
thinking of their potential use in the
medical field.’ Jorge Boczkowski1,2 &
†Author for correspondence
Paris, 7 Denis Diderot, site
Bichat, Paris, France
Tel.: +33 144 856 248;
Fax: +33 144 856 257;
2Assistance Publique –
Hôpitaux de Paris, CIC 007
Hôpital Bichat, Paris, France
1Inserm, part of Carbon nanotubes (CNTs) are cylinders of one
or several coaxial graphite layer(s) (single-walled
[SW]CNTs or multiwalled [MW]CNTs, respectively) with a catalytic material (iron, nickel or
cobalt) often present inside and/or at their
extremity, as well as variable amounts of inert
synthesis support, depending on the synthesis
method . Their diameter is in the order of
nanometers (depending on the number of walls)
and they can reach several micrometers in length.
Owing to their unique electrical properties, unusual strength and particular effectiveness in heat
conduction , CNTs are particularly promising
nanomaterials for industrial use (see  for
inventory) and, therefore, one can easily imagine
that their production will continue to increase in
the future. However, the same novel properties
that make CNTs interesting raise concerns about
their potential adverse effects on biological systems, which could lead to health issues, particularly when thinking of their potential use in the
Potential uses of CNTs in the
There are several applications for CNTs that
could be of major interest in the medical field.
Owing to their semiconducting properties,
SWCNTs have been proposed as chemical sensors for gaseous molecules, such as NO2 or
NH3 . Functionalization of SWCNTs with
polyethylene oxide chains not only overcomes
nonspecific binding of proteins to CNTs but also
further enables the binding of specific proteins of
interest (by conjugation of their specific receptor
to the functionalized SWCNTs), proteins that
can be ultimately detected electronically without 10.2217/17435818.104.22.1687 © 2007 Future Medicine Ltd ISSN 1743-5889 the need for labeling . The authors concluded
that the potential application of this system
could be for the detection of clinically important biomolecules, such as antibodies associated
with human autoimmune diseases, therefore
they proposed CNTs as diagnostic tools.
Another potential application of CNTs to
nanomedicine is their use in the therapeutic field
as vectors for drug delivery. For example, Pantarotto et al. demonstrated that functionalized CNTs
(water-soluble SWCNTs modified with a fluorescent probe) are able to cross the membrane of
fibroblasts in vitro and accumulate in the cytoplasm or reach the nucleus, without any associated
toxicity . Therefore, these systems could help to
solve transport problems for pharmacologically
relevant compounds that need to be internalized
and, for that reason, could find potential therapeutic applications. Another area of application of
CNTs in the therapeutic field is photothermal
therapy for cancer. Indeed, although biological
systems are transparent to 700–110-nm nearinfrared (NIR) light, the intrinsic strong absorbance of SWCNTs in this window can be used for
optical stimulation of CNTs inside living cells to
afford various useful functions . Kam et al. have
shown that this singular property of SWCNTs can
be used to destroy cancer cells selectively upon
irradiation with NIR light. In this study, functionalization of SWCNTs with a folate moiety
and selective internalization of SWCNTs inside
cells labeled with the tumor marker folate receptor was followed by NIR-triggered cell death,
without harming the receptor-free normal cells
. This selective cancer cell destruction by appropriately functionalized SWCNTs provides new
opportunities in the area of cancer therapy.
There is an increasing list of potential applications of CNTs in the medical field, should it be
as diagnostic or therapeutic tools. However, a
major issue occurring with these exponential
applications is the potential inherent toxicity of
CNTs while in biological systems.
What is known about CNT toxicity?
Schematically, there are two situations in which
people could be exposed to CNTs: accidental
exposure, essentially to an aerosol in the context
Nanomedicine (2007) 2(4), 407–410 407 E DITORIAL – Boczkowski & Lanone of CNT production; and exposure as a result of
CNT use for biomedical purposes. To date,
studies on CNT toxicity have focused mainly
on the effects of CNTs administered as a single
dose by the intratracheal or pharyngeal route to
animals, which mostly mimics accidental exposure by inhalation [7–12]. These studies show
that CNTs can induce pulmonary inflammation (elevated inflammatory cell content and/or
inflammatory cytokine production) as well as
the development of interstitial fibrosis [7–9,11].
Some studies, however, nuance those findings,
reporting that the pulmonary inflammatory
response is only transient , or even absent
. Those discrepancies could be related to the
evaluation of different types of CNTs (SW or
MW), CNTs synthesized by different methods
(e.g., high-pressure carbon monoxide proportionation process [HiPco] or chemical vapor
deposition) and CNTs further treated or not
(purification by acidic or basic treatment)
before animal exposure. One in vivo study
raised the possibility of systemic effects of
CNTs after pulmonary exposure. Li et al.
showed that pharyngeal aspiration of HiPcoproduced SWCNTs in mice (10 and
40 µg/mouse) induces aortic mitochondrial
DNA damage, glutathione depletion and
increased formation of protein carbonyl
groups, 7, 28 and 60 days after exposure.
Moreover, administration of SWCNTs
(20 µg/mouse, once every other week for
8 weeks) resulted in an accelerated plaque formation in a model of atherosclerosis in mice
(apolipoprotein [Apo]E-/- mice fed an atherogenic diet) . This study clearly calls for more
research on the potential systemic effects of
CNTs after pulmonary exposure.
Literature regarding in vitro studies on the
biological effects of CNTs is more abundant
and gives some mechanistic insights into the
key factors that influence toxicity. These studies highlight that CNTs can be toxic for macrophages
keratinocytes [17–19], type II alveolar epithelial
cells [13,14,20], mesothelial cells , aortic
smooth muscle cells , skin fibroblasts [23–25]
and embryo kidney cells . In terms of the
intracellular mechanism, oxidative stress is proposed frequently as a key mechanism of CNTinduced toxicity, usually linked to the metallic
impurities of CNTs [14,27,28]. Induction of
apoptosis and/or of an inflammatory response
has been described in some studies [15,18,23,26,29]
but not in others [14,30].
408 Nanomedicine (2007) 2(4) ‘Similar to other nanomaterials, the
intrinsic danger level of CNTs depends on
their physicochemical characteristics.’ What care should be taken in
interpreting CNT toxicity studies?
Similar to other nanomaterials, the intrinsic danger level of CNTs depends on their physicochemical characteristics. This is a complex issue
because, coming back to initial CNT synthesis,
there are a lot of possible end products with different physicochemical characteristics given the
combination of the different synthesis methods
(e.g., arc-discharge or chemical vapor deposition
HiPco), cleaning processes, number of walls
(SWCNTs or MWCNTs), metal catalyst (e.g.,
iron, nickel or cobalt), size (internal/external
diameter or length) and surface modifications
(acidic treatment or functionalization). Although
some information is available concerning the
structure–toxicity relationship of CNTs, some
key physicochemical characteristics of CNTs that
could be a determining factor are beginning to
arise . For example, the acidic treatment of
CNTs, often used to diminish their catalyst content, is associated with increased toxicity [16,24,32].
Another point is the status of CNT dispersion in
solution because CNTs are highly hydrophobic
. Exposure of mice fibroblasts, rat aortic
smooth muscle cells or human mesothelial cells
to well-dispersed SWCNTs is associated with
lesser cytotoxicity compared with the same SWCNTs present in an agglomerated form [21,22,34].
This high hydrophobicity of pristine CNTs has
induced the need for researchers to modify the
surface chemistry of CNTs, namely the ‘functionalization’ process, to improve their aqueous
solubility, which is a very important point in
terms of their subsequent potential toxicity.
Indeed, Sayes et al. demonstrated that the toxicity of SWCNTs functionalized with COOH or
SO3H groups is decreased as the degree of functionalization increases (together with their solubility) . Moreover, Dumortier et al.
demonstrated that NH3-functionalized SWCNTs did not induce any toxicity after their
exposure to mouse B and T lymphocytes and
macrophages in vitro . Only one in vivo
study has assessed the compatibility of such
functionalized CNTs within the biological
milieu. Singh et al. showed that indium-labeled
functionalized SWCNTs administered intravenously to mice followed a rapid clearance from
future science group Potential uses of carbon nanotubes in the medical field – EDITORIAL the blood compartment through the renal excretion route, without any adverse side effects
(absence of renal or other severe acute toxicity and
mortality) . These results are of great interest
when considering the use of functionalized (as
opposed to pristine) CNTs as novel medical tools.
Another critical issue in considering the interpretation of toxicity data is the potential interaction
of CNTs with well-described and well-used viability assays . For example, Wörle-Knirsch et al.
demonstrated recently that SWCNTs can interact
physically with the tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
[MTT]), resulting in a false diminution of MTT
reduction, which leads to the misleading conclusion that the SWCNTs were cytotoxic to human
lung alveolar epithelial cells . Such interference
of CNTs has also been described with other
widely used cytotoxicity assays (i.e., neutral red
incorporation, lactate deshydrogenase or adenylate kinase release) [20,37]. This could explain
the differences observed in some studies when
assessing the toxicity of a single CNT with different tests [13,14,20]. Moreover, CNTs can interact directly with culture medium and its
additives, such as serum , and also with proteins [39–41], and can therefore interfere with
techniques, including enzyme-linked immunosorbent assay (ELISA) dosages . These technical issues have highlighted the potential need
for the establishment of a new specific discipline, nanotoxicology, stressing the necessity to
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Importantly, although the available data are very
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