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Preface
Nanotoxicity and the importance of being earnest☆
In the process of advancing new technologies, in particular those
intended to improve human health, it is not an uncommon observation
that its proponents glorify the benefits with directness while addressing
the unresolved matters in vaguer terms. More often, however, real
progress requires at the very least the ability to fully appreciate overt
or hidden dangers of new medical treatments. In a sense, it is needed
when seeing a spade also to call it a spade. We believe that the successful development of nanomedicines is in no exception to this need.
A spade, however, is an easily visible and identifiable object where
little sophistication is required to assess its potential use or associated
dangers. As tools, nanomedicines are widely different with regard to
the ease in such assessment. The National Institutes of Health defines
nanomedicine as a form of nanotechnology performed at the molecular scale [1]. It was and remains one of the big challenges of the past
and present centuries to visualize – or “see” – the structure of biological macromolecules. The dimensions of nanoparticles are on par with
the dimensions of a large plasma protein. Several lines of investigation suggest that the topological features of the particles permit interaction with proteins in non-trivial ways [2–6]. While these
interactions are likely to be important in the adverse reactions to
the particles, means of characterizing them are scarce. For instance,
although mass spectrometry may serve to address what protein species are deposited on the surface of plasma-exposed particles [7], the
colloidal nature of these particles limits the application of other
methodologies of biochemistry. Imaging of nanoparticles is also
checked by the size, when this is below the Abbe diffraction limit excluding several types of microscopical analyses that in other cases
have been helpful, for example, in understanding the tissue distribution of particulate material. In principle, one would think that the
link between molecular shape and toxicology established through
many years of pharmacological research contributes a straightforward rational extendable to cover nanoparticles as well. However,
the work by Leszczynski et al. shows that no simple ways are likely to
exist of formalizing the assessment of the toxicological hazards
presented by nanostructured materials. Only more complex computational methodologies are ways to resolve this issue safely [8,9].
The spade is easily designed to make its way into the ground.
By contrast, once inside the body the nanomedicines find themselves
in a hostile environment, where considerable ingenuity in design is required to keep the therapeutic potential intact. In itself this may not present a toxicological problem, but a considerable body of evidence points
that it is the immune system of the host incapacitating their function
[10,11]. The immune response in this situation is akin to a type of hypersensitivity reaction, which may trigger violent inflammatory responses.
This way, materials such as carbon nanotubes may cause harm in the
☆ This preface is part of the Advanced Drug Delivery Reviews theme issue on
“Immunotoxicity derived from manipulating leukocytes with lipid-based nanoparticles”.
organs where they are deposited as discussed in several reports by
Boczkowski et al. [12–14]. With regard to characterizing the immune effector mechanisms in action, it is now clear that the innate immune system in several ways is a major contributor to the response to
nanomedicines. Important work by Moghimi et al. identified the complement system as responding vigorously to certain nanostructured liposomes and carbon nanotubes [15–17]. Similar to hypersensitivity
reactions involving complement (Type II and III), the damage is here
caused significantly by the release of anaphylatoxins with ensuing vascular dilation and shock [18,19]. Fortunately, appropriate animal
models for investigating these problems have become available, notably
through the use of pigs as shown by Szebeni et al. [20]. In addition to
complement activation, other parts of the innate immune system also
contribute to adverse immune response to nanomedicine formulations
[21]. Toll-like receptors are evolutionary selected to recognize certain
molecular patterns presented by mostly molecules of microbial origin.
Howard et al. [22,23] and Barros et al. [24] addressed this point with regard to adverse reactions to RNAi-based therapeutics, including failure
of appropriate delivery [23]. Clearly, the sensitivity of Toll-like receptors
to non-self nucleic acids and certain lipids used for liposomal delivery is
an important limitation on the otherwise promising possibilities of
treatment with RNAi [21,25,26]. In a mechanism involving CD14, liposomes made from cationic species may considerably alter the cellular
responses through clustering of the integrins CD11b/CD18 and CD11c/
CD18 as discussed by Lonez et al. [27]. Integrins are strong signaling
molecules [28] and the observations by Lonez et al. together with the
well-described ability of these molecules to interact with a wide variety
of ligands [29] certainly points to integrin-mediated signaling as important in the assessment of the potential toxicity of nanomedicines.
Both the genes encoding proteins of the complement system and the
Toll-like receptors are subject to genetic polymorphism, which is known
to cause considerable differences in the function of the innate immune
system even among healthy individuals [30,31]. Therefore, it is probably
important to take into consideration the detailed functions of the innate
immune system in the treated patients when applying nanomedicines
[29,32]. In this perspective, the new available methodologies for comprehensive genomic characterization and other tools for personalizing medicine may turn out to be an important part of the successful use of
nanomedicine [33]. The immune system may also interfere with drug delivery in a very different fashion. One of the most efficient ways of
targeting select cell types or molecular mechanisms involves the use of
monoclonal antibodies. Their high specificity enables the binding, e.g.,
to certain receptors presented only on the surface of distinct cell
populations. However, as discussed by Litvak-Greenfeld and Benhar
[34], depending on the format of the targeting antibody and the receptors targeted significant side effects may arise from the unwanted activity of leukocytes binding to the antibody or from consequences of the
antibody binding receptors this way disturbing their biological function.
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http://dx.doi.org/10.1016/j.addr.2012.09.002
Please cite this article as: T. Vorup-Jensen, D. Peer, Nanotoxicity and the importance of being earnest, Adv. Drug Deliv. Rev. (2012), http://
dx.doi.org/10.1016/j.addr.2012.09.002
2
Preface
A simple way of avoiding unwanted immune or other responses to
nanomaterials involves the choice of materials, where physiological
mechanisms in the body are able to handle the material appropriately.
The possibilities of using silicium-based materials are interesting, not
only because of the elegant chemistry for regulating the size of the particles and surface modifications, but also because their degradability within
the body [35]. However, as discussed by Godin et al., certain aspects of the
genotoxicity are not fully explored [35,36]. In a wider perspective, as thoroughly researched by Kingshott et al., the materials science perspective on
nanomedicine is important to maximize biocompatibility, also with regard to avoid adverse activation of immune responses [37–39]. It is
clear from this line of research that biointerfaces involving engineered
surfaces are influenced qualitatively and quantitatively by properties of
the nanotopography. This offers a truly nanotechnological perspective
on what may be achievable by structuring surfaces at the nm-scale and
extends the venues of nanomedicine well-beyond drug administration.
Taken together, the toxicology of nanostructured materials is challenging to understand and master. As a starting point, an earnest approach must acknowledge this complexity to make nanomedicine
work in a safe manner. From the current literature it is clear that no
single methodology is likely to meet all of the important challenges.
Rather, nanotoxicology is best studied through an interdisciplinary
effort involving pharmacological risk assessment schemes, materials
science engineering, appropriately selected animal models, as well
as insight on drug delivery vehicles and the inner cellular and biochemical workings of the immune response to foreign materials.
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Thomas Vorup-Jensen
Theme Editor⁎
Biophysical Immunology Laboratory, Department of Biomedicine, Aarhus
University, Aarhus, Denmark
The Lundbeck Foundation Nanomedicine Center for Individualized
Management of Tissue Damage and Regeneration, Aarhus University,
Aarhus, Denmark
Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
Correspondence to: T. Vorup-Jensen, Department of Biomedicine,
Aarhus University, The Bartholin Building (1240), Wilhelm Meyers
Allé 4, DK-8000 Aarhus C, Denmark.
E-mail address: [email protected].
Dan Peer
Theme Editor⁎⁎
Laboratory of NanoMedicine, Department of Cell Research and
Immunology, George S. Wise Faculty of Life Science, Tel Aviv University,
Tel Aviv, Israel
Center for Nanoscience and Nanotechnology, Tel Aviv University,
Tel Aviv, Israel
Correspondence to: D. Peer, Department of Cell Research and
Immunology, Tel Aviv University, Tel Aviv 69978, Israel.
E-mail address: [email protected].
Available online xxxx
Please cite this article as: T. Vorup-Jensen, D. Peer, Nanotoxicity and the importance of being earnest, Adv. Drug Deliv. Rev. (2012), http://
dx.doi.org/10.1016/j.addr.2012.09.002