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Metaphors in Nanomedicine: The Case of Targeted Drug Delivery

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Abstract

The promises of nanotechnology have been framed by a variety of metaphors, that not only channel the attention of the public, orient the questions asked by researchers, and convey epistemic choices closely linked to ethical preferences. In particular, the image of the ‘therapeutic missile’ commonly used to present targeted drug delivery devices emphasizes precision, control, surveillance and efficiency. Such values are highly praised in the current context of crisis of pharmaceutical innovation where military metaphors foster a general mobilization of resources from multiple fields of cutting-edge research. The missile metaphor, reminiscent of Paul Ehrlich’s ‘magic bullet’, has framed the problem in simple terms: how to deliver the right dose in the right place at the right moment? Chemists, physicists and engineers who design multi-functional devices operating in vitro can think in such terms, as long as the devices are not actually operating through the messy environment of the body. A close look at what has been done and what remains to be done suggests that the metaphor of the “therapeutic missile” is neither sufficient, nor even necessary. Recent developments in nanomedicine suggest that therapeutic efficacy cannot be obtained without negotiating with the biological milieu and taking advantage of what it affords. An ‘oikological’ approach seems more appropriate, more heuristic and more promising than the popular missile. It is based on the view of organism as an oikos that has to be carefully managed. The dispositions of nanocapsules have to be coupled with the affordances of the environment. As it requires dealing with nanoparticles as relational entities (defined by their potential for interactions) rather than as stable substances (defined by intrinsic properties) this metaphor eventually might well change research priorities in nanotechnology in general.

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Notes

  1. Interviews with Patrick Couvreur (Institut Galien Université Paris-Sud), Florence Gazeau (Laboratoire matière et systèmes complexes, Université Paris Diderot) and Ania Servant (Nanomedicine Laboratory, University College London School of Pharmacy).

  2. In Rorty’s pragmatic philosophy, language is ‘image-schematic’ but it is not a representational ‘mirror of nature’: it is ‘formative’, i.e.: giving instructions to others about to give form to something, and per-formative, i.e.: being ‘instructive’ in that sense.

  3. Because all individuals are not responding to the same drug, personalized medicine is looking for molecular signatures—so called ‘biomarkers’—that would allow to direct different categories of patients to more adapted therapies, possibly on the basis of early diagnoses (molecular biomarkers are anything that can be detected and used for measuring the probability of incidence of a disease, its progress, or its treatment’s effects: DNA or RNA single nucleotide polymorphism, protein, complex of proteins, or changes in protein expression).

  4. Personalized medicine seeks to specify therapy by means of profiling and stratification: It sets up distinct categories of patients with regard to their probability of better responding to this or that therapy on the basis of tests determining the presence of a biomarker. It is to form categories of patients fitting with prescriptions and conversely to adjust prescriptions to categories of patients. Targeted drug delivery, by contrast, starts from a given molecule and a given target (organ, tissue, cell, organelle or molecular receptor) and seeks the most fitting nanoscale formulation to carry the molecule to the target.

  5. Currently, the innovation landscape of nanovectorization is mostly populated with small start-ups selling their patents to big pharmaceutical companies [77]. They rely on venture capitals and business angels to bear the costs of preclinical development, scaling-up studies, upgrading to legal standards, and phase-I to mid-phase-II trials. Big pharmas cover only end-phase-II and phase III. They adopt a ‘wait-and-see’ strategy ([97]: 4) and refuse to rush head down towards a disruptive technology unless it has pugnaciously proven its safety and efficiency [15].

  6. It is expected that targeted drug delivery will provide pharmaceutical industry with new patents thanks to the nanoformulation of established molecules before the end period of their IP rights. It also allows patenting older medicines that so far could not enter the market ([4, 97]: 3).

  7. Here we take the two rival founding fathers as mythical figures. It matters little to us whether Galen and Paracelsus were really what their heirs have made of them. The master narrative built on the two heroes are still framing pharmacological culture.

  8. Ehrlich wrote that “If we picture an organism as infected by a certain species of bacterium, it will obviously be easy to effect a cure if substances have been discovered which have an exclusive affinity for these bacteria and act deleteriously or lethally on these alone, while at the same time they possess no affinity for the normal constituents of the body and can therefore have the least harmful, or other effect on that body. Such substances would then be able to exert their full action exclusively on the parasite harboured within the organism and would represent, so to speak, magic bullets, which seek their target of their own accord” (Ehrlich [27], p. viii).

  9. Significantly, twentieth century Galenics refers to the ‘formulation’ of drugs, i.e.: making tablets, suppositories, creams or syrups, according to a specific procedure called a ‘formula’ (a medicinal form suitable for administration). Galenics is often despised by modern pharmacology as being concerned with external form or packaging instead of active principles, as being technique or even marketing, not science—a rather unfair view, since it is Galenics that allows the transformation of a mere ‘drug’ into a proper ‘medicine’. Galenic pharmacy is indeed indispensable for the standardisation of doses and posology as well as for the stabilisation and conservation of active substances [87]. Galenics is the art of taming substances.

  10. The encapsulation rate is one of the major bottlenecks for the technique. Currently, most systems do not exceed a rate of 10 % of active principles encapsulated on the total amount of nanoparticles synthesized, which limits both their cost-efficiency and therapeutic index.

  11. Actually, Norbert Wiener’s conceptualization of feedback or retroaction originated in his warfare research on self-guided devices during World War II [32].

  12. Originally coined to refer to a treatment platform combining a diagnostic test setup with a therapy based on the evolution of the test results [100], theranostic nanomedicine is now defined as ‘an integrated nanotherapeutic system which can diagnose, deliver targeted therapy and monitor the response to therapy’ ([95], p. 137).

  13. Here, ‘robot’ clearly means an enslaved machine-tool, not an independent automaton. This is not surprising, since, as Nerlich argues [72, 73], the images of nanobots cleaning fats in blood vessels are recycling the older visual archetypes of shrunk humans travelling through the body, as shown in the movie The Fantastic Voyage. Nanomedicine’s imaginary has replaced shrunk surgeons and their tools with miniaturized robots. In turn, the focus has shifted ‘from the “extraordinary” (voyages) to the “ordinary” (medicine), thereby contributing to the normalisation of nanomedicine and its integration into normal biomilitaristic medical discourse’ [74]. The metaphor of the nanorobot has had to be ‘militarized’ to move from pure science fiction to something real, serious, and valued by our society.

  14. A striking example of fusion between drug and device is the NanoXray™ developed by the French start-up Nanobiotix (http://www.youtube.com/watch?v=kxSX6YJTS2I), in which the nanoparticles amplify the physical mode of action of radiotherapy. NanoXray™ is like a nanoscale extension of the radiotherapy setup internalized in the patient’s body to relay and locally amplify its effect. This conflation is also visible in the normative framework of regulation under which the development of NanoXray™ is placed: under the category ‘drug’ by the US FDA and under the category ‘medical devices’ by the French AFSSAPS. This later regime of regulation would, if not accelerate, at least facilitate NanoXray™’s entrance in the market by bypassing the ever-expanding ‘valley of death’ of pharmaceutical development. As a venture capitalist investing in the start-up put it on one of the Nanobiotix’s site podcasts, ‘I believe we are getting a biotech care company potential with a medical device time-to-market’ (http://www.nanobiotix.com/about-us/).

  15. The nanocarriers obtained by ‘squalenization’ by Couvreur and his team instantiates the identification of the drug with its Galenic formulation. Squalene, a biological organic compound, can chemically bind with the anticancer drug gemcitabin, thus forming a new molecular entity, gemcitabine-squalene, which in turn self-assembles into nanoparticles in water [84].

  16. On the difference between abstract and concrete engineering views in nanotechnology see [5] 79–82).

  17. Efficacy is generally defined as the ability to bring about a desired effect, whereas efficiency measures the ratio of beneficial output (e.g.: useful fork, economic profit) versus (the amount of means/resources) involved (time, energy, effort, costs…). Therapeutic efficacy is the main concern in the development process (where it becomes the most important criterion).

  18. To be sure, military missiles sometimes release munitions without homing devices, at random, in the hope that enemy targets will be affected by statistics. But they don’t have the glamour of surgical strikes.

  19. Even when the drug carrier is equipped with specific antibodies, peptides or ligands, these so-called ‘homing devices’ do not point only to a target receptor, but also sometimes to a relay receptor enabling the nanovector to cross a biological barrier. For instance, when decorated with the specific antibody of the transferrin receptor, chitosan nanospheres can cross the blood–brain barrier for delivering biologically peptides to the brain [52]. In this case, a temporary alliance is contracted with a smuggler afforded by a particular biological milieu.

  20. Enhanced Permeability and Retention is the effect of inflammation, which induces the arrival of macrophages and the release of cytokines increasing the permeability of vessels.

  21. This is the case of the palmarplantar erythrodysesthesia or ‘hand-foot syndrome’. Hands and feet are usually subjected to mechanical pressure and friction, which causes instantaneous dilatation of the endothelial tissue of blood vessels which, similarly to the EPR effect. Yet this allows the nanocarriers to locally cross the endothelial wall of healthy tissues. The areas affected become red, dry, peel, numb or painful, with possible necrosis. This unwanted leakage of the nanocarrier can be attenuated by modifying some everyday activities (avoiding wearing tight clothes, using tools, jogging, taking hot showers or being exposed to strong sunlight). But for very sensitive patients such an adverse effect unfortunately limits the maximal safe Doxil® dose that can be administrated as compared with doxorubicin in the same treatment regime.

  22. For this purpose, lentil-shaped liposomes were designed to release their content only under the high shear stress found in constricted blood vessels [47, 56].

  23. To attribute a dispositional property to a thing amounts to saying that if certain conditions are obtained, then that thing will behave in a specific manner or bring about a specific effect. For instance ’a negatively charged particle is one of which it is true that, if brought into proximity to another negatively charged particle, it will experience a force of repulsion’ ([41], p. 97).

  24. The term affordance coined by James J. Gibson in the context of animal psychology combines generic material dispositions and specific intentions and purposes. In Gibson’s ecological theory of perception, affordances are the possibilities of action that are offered to an agent by an environment [38]. The concept has also been used in design theory, to express how objects invite and constrain their users by offering ‘cues for action’ [23, 76].

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Acknowledgments

We are grateful to Patrick Couvreur, Florence Gazeau, Ania Servant, Cyril Bussy, and Brigitte Nerlich.

Funding Sources

The research for this paper has been conducted by the authors with the help of ANR-project Nano-2E ANR-09-NANO-001-02.

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Authors and Affiliations

  1. CETCOPRA, Paris, France

    Bernadette Bensaude Vincent & Sacha Loeve

  2. Université Paris 1, Paris, France

    Bernadette Bensaude Vincent & Sacha Loeve

  3. IUF, Paris, France

    Bernadette Bensaude Vincent

Authors
  1. Bernadette Bensaude Vincent
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  2. Sacha Loeve
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Correspondence to Bernadette Bensaude Vincent.

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Bensaude Vincent, B., Loeve, S. Metaphors in Nanomedicine: The Case of Targeted Drug Delivery. Nanoethics 8, 1–17 (2014). https://doi.org/10.1007/s11569-013-0183-5

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  • DOI: https://doi.org/10.1007/s11569-013-0183-5

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