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ADR-12364; No of Pages 2 Advanced Drug Delivery Reviews xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr 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. 0169-409X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. 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. 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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