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Quo Vadis Nanomedicine?
Quo Vadis Nanomedicine? University of Exeter, Exeter, UK, 10–11 April 2014
Robert Luxenhofer1, Matthias Barz2 & Michael Schillmeier*,3 Functional Polymer Materials, Chair for Chemical Technology of Materials Synthesis, Julius-MaximiliansUniversity Würzburg, Röntgenring 11, 97070 Würzburg, Germany 2 Institute for Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10–14, 55099 Mainz, Germany 3 Department of Sociology, Anthropology & Philosophy, Centre for the Studies of Life Sciences, University of Exeter, Byrne House, Exeter, EX4 4PJ, UK *Author for correspondence:
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The interdisciplinary workshop ‘Quo Vadis Nanomedicine?’ was held on 10–11 April 2014 at the University of Exeter (Exeter, UK), coorganized by the Schumpeter-Research Group ‘Innovations in Nanomedicine’, funded by the VolkswagenStiftung at Exeter University, and the Sonderforschungsbereich (STB; collaborative research centre) 1066 ‘Nanodimensional Polymer Therapeutics for Tumor Therapy’, funded by the German Research Council (DFG) at the Johannes Gutenberg-University (Mainz, Germany). This international workshop brought together scientists, philosophers and social scientists in order to reflect, discuss and rethink the practices, concepts, methods, models and metaphors, as well as the medical and regulatory needs in current nanomedical research and its possible futures.
Nanotechnology has received significant attention from researchers, funding agencies, regulatory bodies, science and technology studies and the general public over recent decades. In general, it has been perceived as a most promising field of innovative research, but it also raises concerns regarding risks and safety, as well as social, legal and ethical issues. With significant funding, nanomedical research in particular is meant to overcome the limited therapeutic successes of classical low-molecular-weight drugs in cancer, Alzheimer’s disease, diabetes, HIV, cardiovascular disease and many other diseases. However, arguably, the research progress lags behind the great expectations that have been formulated for decades, even before the ‘invention’ of the nanolabel. The translation of promising worldwide research activities into clinically approved therapeutics has been slower than anticipated and draws attention to the complexity of nanosized system–environment processes and relationships. The first polymer–drug conjugates were described as early as 1954 [1] . Already in 1975, Ringsdorf summarized the ideas regarding polymer-
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based drug delivery and therapeutic systems [2] . This seminal paper still influences many colleagues and design principles in nanomedicine. Despite this time frame, the vast majority of the approved nanomedical pharmaceuticals fall into a few categories, in particular antibodies, PEGylated proteins and a few polymers. More complex systems, such as polymer–drug conjugates, polymer micelles, nanohydrogels and (multi)functional organic or inorganic colloids are seen as promising ‘smart drugs’, but are not broadly available for patients so far. Consequently, nanomedical research finds itself within an ambivalent situation where high promises face moderate clinical successes. In his introductory note, M Schillmeier (University of Exeter, Exeter, UK) developed a framework of how to publicly engage with nanomedicine research in order to address and shape the scientific and societal issues of current and future nanomedical research. Outlining the concept of ‘publics’, this workshop can be understood as a productive way of questioning, disputing and complicating the excessive ‘culture of promise’ of nanotech-
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Conference Scene Luxenhofer, Barz & Schillmeier nology, and instead focusing on the complexities, issues and uncertainties of nanomedical research practices. One of the most common terms used in the workshop (besides ‘nano’) was the term ‘complexity’. Interestingly, this term was employed in several different contexts. Complexity in making nanomedicines At the start of every nanomedicine is the process of synthesis and characterization, which needs to be based on medical, biological and translational needs. Polymer chemists R Zentel (University Mainz, Mainz, Germany) and R Haag (Free University of Berlin, Berlin, Germany) discussed the different approaches to creating carriers, which are either of a self-organization or chemical design. They both pointed out the dilemma that whenever you desire defined complex structures, your complexity at all levels increases dramatically, and the development of a carrier system often needs to combine both approaches, especially when the nanoparticle’s size increase to several tenths of nanometers. The theme of complexity was picked up and further developed by R Luxenhofer (University of Würzburg, Würzburg, Germany) and M Barz (University of Mainz, Mainz, Germany) in the context of rational design and high-throughput screening. By comparing rational design and high-throughput methods, Luxenhofer and Barz discussed the possibilities that pertain to the complexity of understanding biological systems and the development of nanomedical systems. In the complex environment of an organism, rationally based predictions appear to be intrinsically difficult, and thus highthroughput methods can facilitate the development of nanomedicines. This method, however, can become misleading or simply useless when it is based on systems in which a given readout cannot be related to a chemical structure due to the high dispersity of the molecules and/or particles involved [3] . Pharmacologists and oncologists T Lammers (RWTH Aachen, Germany), F Kiessling (RWTH Aachen, Aachen, Germany) and B Metselaar (University of Twente, Enschede, The Netherlands) critically discussed the future relevance and requirements of nanomedicine research with respects to patients’ needs as researchers tend to create ever more sophisticated nanomedicines that are, in their view, unlikely to be successfully implemented into clinical reality [4] . They emphasized that the most sophisticated nanoparticle design may be useless if it cannot be translated or simply does not address medical needs. This point was emphasized by S Rannard and R Owen (both University of Liverpool, Liverpool, UK). They presented their work on conceptually modest but technologically advanced, orally available antiretrovirals for HIV, which will pro-
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ceed to clinical trials at the end of this year. They also emphasized that, with a view towards translation, the design of nanomedicines needs to be kept as simple as possible. Therefore, even higher efficiency can be easily compromised by higher complexity. Furthermore, from a physicochemical point of view, K Landfester (Max Planck Institute for Polymer Research, Mainz, Germany), M Schmidt (University of Mainz, Mainz, Germany), W Parak (University of Marburg, Marburg, Germany) and F BaldelliBombelli (University of East Anglia, Norwich, UK) subsequently discussed the methods to better understand the interactions of nanoparticles with complex biological media, which may shape to the properties of nanoparticles to a larger extent than synthetic chemists imagine. They clearly demonstrated how different methods interfere with the research process and shape its outcomes. An analytical method can be rather precise; for example, fluorescence correlation spectroscopy can be used in order to investigate protein absorption on fluorescent nanoparticles in a size range of approximately 10 nm in a quantitative manner, while the method fails for larger systems and alternatives are needed. Although dynamic light scattering can today performed in blood serum, the method is also insufficiently precise for the investigation of the adsorption of single proteins on the surface of nanoparticles in the size range of 30–200 nm. While isothermal titration calorimetry can help us to study adsorption related to heat flow, to date, it appears impossible to dissect the heat flow in complex protein mixtures, such as blood. In summary, all speakers pointed out the complexity in synthesis and characterization, underlining the need for simplicity in making and combining various analytical methods when analyzing nanomedicines. Complexity of models & processes in nanomedicine Although the final objective of every nanomedicine should be to improve the quality of life of patients, the road to this goal is a long and often nonlinear trajectory. On this journey, a crucial factor – or perhaps the most crucial one – is employing and improving meaningful models in order to steer the development of therapeutic systems. With respect to this, chemist N Tirelli (University of Manchester, Manchester, UK) presented how nanomedical research that is already in vitro – one being cellular (the role and nanoscale morphology of a splice variant of fibronectin in myofibroblasts) and one being acellular (the responsiveness of nanoparticles to reactive oxygen species) – easily produces unintended effects and thus requires precise and carefully performed control experiments in order to adequately
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Quo Vadis Nanomedicine?
address the complexity of biological systems, which cannot be avoided. Pharmacologists C-M Lehr (Saarland University, Saarbrücken, Germany) and A Lamprecht (University of Bonn, Bonn, Germany) presented their research and views on the noninvasive delivery of nanomedicines and novel in vitro models. It was stressed that the fate and characteristics of nanoparticles may depend on their route of entry into the body, which is of considerable importance in nanosafety and nanotoxicology. In addition, the finding of meaningful in vivo (animal) models – the inherent problem of pharmaceutical development – was discussed. This point, however, is widely known, but the complexity of in vitro experiments also requires consideration and may close the gap in understanding of the failure of nanomedicines in vivo. Nanomedical complexity in toxicology, safety & clinical translation Besides optimization, therapeutic efficacy determination of toxicology (safety) determines the therapeutic window for every drug. Thus, with respect to nanomedicines, adverse effects can compromise the best efficacy. Thus, detailed toxicology is essential before clinical translation in order to ensure basic safety requirements are met. The safety issues of complex nanosystems and their environments were highlighted by V Stone (HeriotWatt University, Edinburgh, UK). She discussed the relationship of in vitro and in vivo models in nanotoxicology, and how in vitro models may be improved. She also showed how nanotechnology, nanomedicine and nanotoxicology transformed a traditional and formerly rather small field of study – that of particle toxicology. The influx of significant funds into what became nanotoxicology leveraged a marked change in methods, tools and targets. The future is likely to bring even more tools and more refined methods and it is expected that the field will make important contributions to nanomedicine. The relationship between nanomedical research and toxicology has been the main focus of the sociologist G PourGashtasbi (University of Exeter, Exeter, UK). Her ethnographic work traced the complex questions and issues that arise from the processes of translating medical research practices that deal with and configure nanoscaled objects and how these practices challenge and modify toxicology as a discipline. Biologist T Bopp and physician V Mailänder (both University of Mainz, Mainz, Germany) discussed the promise of nanomedicine in relation to the modulation of the immune system and the use of cells as therapeutic agents. They clearly demonstrated that many of the
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these approaches may require minimal amounts of therapeutic agents effecting a small number of cells and less complex administration routes (e.g., transdermal delivery). Although the immune system itself differs between patients and adaptive immunity will add another level of complexity to in vivo models, immune therapies hold great promise for the application of nanomedicines [5] . Complexity in nanomedicine regulation & Global issues of health & disease For many years, the discussion regarding the definition of nanotechnology in general and nanomedicine in particular has been ongoing. Part of this as-yet unresolved discussion was how regulators should react to the emergence of nanotechnology in the health sector, if at all. In this context, DM Bowman and J Gatof (both University of Michigan, MI, USA) discussed the international regulatory barriers and questions in terms of nanomedicine. Bowman and Gatof argue that adequate resources of the safety regulatory agencies are necessary in order to enable them to perform their functions in a timely and informed manner, as with the agencie that are responsible for assessing intellectual property claims. This will encourage investment, innovation and promote better public health outcomes. The philosopher A Schwarz (ETH Zürich, Zürich, Switzerland) argued that ‘health’ has become an almost irresistible tool in science policy, particularly when it comes to research and development issues in emerging technologies, such as nanomedicine, where it fuels an economy of promises. She discussed how people make sense of the medical culture, its language and values, the modes of knowing and, mainly, how they image and imagine the intrinsically related concepts of health and disease. Schwarz argued that medical knowledge is not only deeply socially conditioned, but it is also built around the conceptual juxtaposition of health and disease that affords fictitious images. This language game acknowledges that concepts of disease being time dependent and denoting multifactorial phenomena. D Robinson (TEQNODE Ltd, Paris, France) outlined a variety of analytic tools and mechanisms of how to achieve responsible forms of nanomedical innovation with which to orient research more effectively in terms of societal needs and ethical concerns. The term ‘personalized medicine’ was discussed by philosopher X Guchet (Université Paris 1, Paris, France). He highlighted the ambivalence of personalized medicine in nanomedicine, which is meant to make ‘technoscientific medicine’ more humane, as well as triggering epistemological and organizational changes in technomedicine. Moreover, Guchet emphasized that personalized medicine does not indicate a linear process towards person-centered medicine, as
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Conference Scene Luxenhofer, Barz & Schillmeier opposed to organ-centered medicine. Rather, it functions as an umbrella for global transformations in healthcare systems, leading to new concepts of the ‘person’ and the responsibility of each individual for their own healthcare status. Expressing nanomedical complexity: visions & language Images, metaphors, visions and visualizations have always been of great importance in the interface of science and medicine. An early example is the name we have in some European languages for neoplastic malignancies. To Hippocrates, the ulcers were reminiscent of crustaceans, thus the term cancer. Another example is the ‘magic bullets’ of Paul Ehrlich [6] . Today, thousands of papers are published every year reporting work in ‘smart drugs’ and ‘targeted delivery’ or ‘controlled release’. Philosopher S Loeve (Université de Paris, Paris, France) discussed the use of war metaphors in bioscience and nano-enabled drug delivery. He also showed that current developments indicate a shift from metaphors of war to those of oikos, whereby oikos reflects the need to address the complex system–environment relationships of embodied processes. Evaluating the two metaphorical frameworks – ‘war’ versus ‘oikos’ – Loeve analyzed their descriptive, performative as well as normative powers. Nanomedical research cannot be understood as a neutral endeavour for the discovery of the laws of nature. Rather, it must be understood as a sociocultural set of ideas, preferences, images and practices that enact specific forms of understanding and performance of biomedical processes, health and illnesses. The complexity of nanomedical interventions was discussed in yet another context by R Pierce (Harvard University, MA, USA). Pierce raised fundamental questions of how to understand health and disease in contemporary societies and how nanomedical research may alter our understanding of it. Nanomedical research also cannot be understood without the visions incorporated in different research designs, which are often governed by an excessive and ambiguous culture of promises. Sociologist N Kubischok (University of Duisburg-Essen, Duisburg and
Essen, Germany) presented, discussed and assessed the rhetoric and mechanisms of future visions and how these visions shape emerging nanomedical technologies, as well as the everyday practices of scientific work. Pharmacologist IS Ferreira (Universidade de Lisboa, Lisbon, Portugal) presented yet another perspective of nanomedicine. From her work as a community pharmacist and as a PhD student, she drew upon the unrealized hopes of patients and PhD students, which have been fostered by the culture of promises of nanomedicine, as nanomedical research often fails. She argued for the need to restructure, reassess and readjust the research processes, involving all the relevant actors (including patients). The extensive discussion between different participants demonstrated the need for more publically engaging events such as these in order to reflect and shape nanomedical research in real time. Similar events should extend the list of relevant actors (i.e., patients, doctors, nurses, nongovernmental organizations, industry and regulators, among others). Acknowledgements The authors would like to thank the SFB 1066 steering committee members S Grabbe, K Landfester, D Schuppan and R Zentel for their encouraging support and advice. C Wong, K Franke, E Fleischmann, T Goodsir and J Ruiz are acknowledged for the organization of the workshop.
Financial & competing interests disclosure The authors would like to thank the Schumpeter-Research Project ‘Innovations in Nanomedicine’, funded by the VolkswagenStiftung at the University of Exeter, and the Collaborative Research Centre ‘Nanodimensional Polymer Therapeutics for Tumor Therapy’ (SFB 1066), funded by the German Research Council (DFG) at the Johannes Gutenberg-University Mainz, for financial support, as well as the British Society for Nanomedicine for additional support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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