In 2010, the Journal of Internal Medicine published a collection of review articles on the application of nanotechnologies in regenerative medicine and drug delivery ( and references therein). The series also included reviews on nanotoxicology. Toxicology or safety assessment is certainly an integral part of any new medical technology, and the nanotechnologies are no exception. The fact that nanomaterials are similar in size to intra- and extracellular biological systems yet can be engineered to have various functions makes these materials attractive for medical applications . However, the same, novel properties that arise at the nanoscale may also lead to unexpected toxicities of nanomaterials, that is, toxicities not anticipated from materials of the same composition in bulk form. Thus, nanotoxicology is emerging as a scientific discipline with the aim of studying the undesirable interference between man-made or engineered nanomaterials and the nanoscale machineries of biological systems . It is important to ask whether there are any unique toxicities or phenomena associated with nanomaterials; the answer is yes. Indeed, as recently pointed out , one of the key features of nanomaterials, and one that may suggest novel and unanticipated health risks, is the propensity of such materials to cross biological barriers. In other words, the geography of the biological response (due to translocation of nanoparticles to organs and tissues distal to their portal of entry into the human body) may be as important as the anatomy of the nanoparticle itself (i.e. the chemical composition of the nanoparticle, along with its size and shape, and so on).
No medicinal product is free of risk; the remit of regulatory agencies is to ensure that medicinal products exhibit an acceptable risk-benefit profile . The aim of nanosafety research in this context is to enable safer design of nanomedicines. It is noted that ‘safe-by-design’ may be a utopian ambition, whilst ‘safer-by-design’ is a more realistic goal; modifying (nano)materials to make them completely ‘safe’ (nonreactive in a biological system) may not be possible and would not make sense if the desirable properties of the materials are lost in the process. To achieve safer design of nanomedicines requires an understanding of material intrinsic properties (the ‘synthetic identity’) along with an understanding of the behaviour of these materials in living systems (the ‘biological identity’) . According to Paracelsus, the dose makes the poison, but when dealing with nanoparticles, one also needs to take into account, for example, the size, shape, solubility and crystallinity, and how these physicochemical properties contribute to the potential toxicity of the material in question. Recent research has suggested that the so-called corona of biomolecules adsorbed onto the surface of nanomaterials may dictate the biological (and toxicological) behaviour of these materials . The nature of the biocorona is likely to differ depending on the portal of entry, for example via inhalation into the lungs or via injection into the blood stream. It has been suggested that the biocorona could mask targeting ligands on nanoparticles, thereby preventing specific uptake by cells that express receptors for such ligands . This certainly has implications for the design of nanoparticles for targeted delivery of therapeutic and/or imaging agents. However, more research is needed to fully understand the impact of the biocorona on the behaviour of nanoparticles. The cost benefit of producing multifunctional nanoparticles for drug delivery with targeting and imaging moieties (so-called theranostic nanoparticles) was recently highlighted . Notably, incorporating additional functionality means additional steps and costs for synthesis of the materials, but also more regulatory hurdles.
Günter Oberdörster reviewed the state-of-the-art in the field of nanotoxicology in 2010 . He discussed concepts of nanotoxicology of relevance for safety assessment and development of industrial applications of nanotechnology including the important issues of dose metrics and biokinetics, that is, the movement and distribution of nanomaterials in the body, as well as the urgent need for validated means of extrapolating acute in vitro results for the prediction of chronic in vivo effects. Of note, there is also a need to shift from traditional, descriptive toxicology to a predictive toxicology; this is true both for chemicals in general and for nanomaterials in particular. To this end, new approaches are needed . In fact, as recently noted, ‘there is almost no other scientific field in which the core experimental protocols have remained nearly unchanged for more than 40 years’ . Specifically, in nanotoxicology, we are faced with a virtual onslaught of new nanomaterials, and therefore, traditional studies addressing one material at a time are no longer feasible if the timely and safe development of nanotechnology is to be promoted. Moreover, alternative approaches that enable the reduction or refinement of traditional animal testing of chemicals or nanomaterials are needed; it is not justifiable from a practical, economical or ethical point of view to test each and every chemical or nanomaterial in animals, and in vitro screening to triage these substances is therefore required. In a very timely review article in the current issue of the Journal of Internal Medicine, Dr. André Nel from the University of California, Los Angeles (UCLA), discusses a predictive toxicological approach for the safety assessment of engineered nanomaterials . The backdrop for this review is the so-called 21st century vision for testing of chemicals which calls for the integration of high-throughput screening (HTS) and computational toxicology approaches into the testing programme, to allow prioritization of chemicals for further testing and to assist in prediction of risk to humans . The aim of the predictive toxicology approach that is promoted is to perform hazard assessment of vast numbers of nanomaterials using a mechanism-based or pathways of toxicity (POTs) approach . The successful implementation of this methodology is predicated on the use of in vitro-based HTS and on the careful selection of POTs at the cellular level that are reflective of pathogenic effects at the organismal level. Importantly, as discussed by Nel, the linkage of nanomaterial physicochemical properties to mechanism-based biological or toxicological outcomes at the cellular level allows for the establishment of so-called structure–activity relationships (SARs) which in turn provides a tool for safety assessment of nanomaterials and for safer-by-design approaches for new nanomaterials. However, as is also acknowledged by Nel, validation of the alternative in vitro-based test methods that form the foundation of the predictive toxicological approach could be a lengthy procedure. Nonetheless, efforts are being made in this direction not only in the USA , but also in Europe within the Framework Programme of the European Commission, and alliances are being forged to improve communication and sharing of results between researchers in nanotoxicology (see, for instance, www.us-eu.org). In summary, Nel provides a vision for a systems toxicology approach in nanotoxicology that may be of particular relevance for nanomedicine, a field in which increasing numbers of ever more sophisticated nanomaterials are being produced, all of which will need to demonstrate an acceptable risk–benefit profile .
The application of nanotechnology in medicine aka nanomedicine is widely anticipated to provide solutions to many unsolved clinical problems and is playing a growing part in pharmaceutical research and development . The issue of nanomaterial toxicity in this context is not ‘controversial’ ; safety assessment is an integral part of any development of new medicines or technologies. The questions are as follows: will nanomedicine deliver on its promise? and which are the most prominent applications of nanomedicines today and in the near future? Etheridge et al. recently provided a very interesting inventory of investigational and approved nanomedicines . They concluded that the field is still relatively adolescent and suggested that the truly transformative capabilities ascribed to nanomedicine are yet to be realized. Notwithstanding, the authors observed a pronounced focus on cancer treatment and on various approaches to achieve active or targeted delivery. Regenerative medicine is frequently highlighted as an area of development, but Etheridge et al. found only two nanomedicine applications related to tissue regeneration . Nanomedicines are also being explored to enhance imaging of disease processes, and Etheridge et al. noted that the next phase is likely to take advantage of combined applications in the form of multimodal treatment (nanomedicines combined with conventional treatments) and theranostic ‘platforms’ (single nanomedicine applications with multiple modes of action). Thus, whilst the prospect of ‘nanorobots’ or nanomachines capable of theranostics in humans seemed remote only a few years ago, this may become a reality sooner than anticipated (Fig. 1).