metaphors in nanomedicine: the case of targeted drug delivery
TRANSCRIPT
ORIGINAL PAPER
Metaphors in Nanomedicine: The Case of Targeted DrugDelivery
Bernadette Bensaude Vincent & Sacha Loeve
Received: 8 June 2013 /Accepted: 4 November 2013 /Published online: 5 December 2013# Springer Science+Business Media Dordrecht 2013
Abstract The promises of nanotechnology have beenframed by a variety of metaphors, that not only channelthe attention of the public, orient the questions asked byresearchers, and convey epistemic choices closelylinked to ethical preferences. In particular, the imageof the ‘therapeutic missile’ commonly used to presenttargeted drug delivery devices emphasizes precision,control, surveillance and efficiency. Such values arehighly praised in the current context of crisis of phar-maceutical innovation where military metaphors foster ageneral mobilization of resources frommultiple fields ofcutting-edge research. The missile metaphor, reminis-cent of Paul Ehrlich’s ‘magic bullet’, has framed theproblem in simple terms: how to deliver the right dose inthe right place at the right moment? Chemists, physicistsand engineers who design multi-functional devices op-erating in vitro can think in such terms, as long as thedevices are not actually operating through the messyenvironment of the body. A close look at what has beendone and what remains to be done suggests that themetaphor of the “therapeutic missile” is neither suffi-cient, nor even necessary. Recent developments innanomedicine suggest that therapeutic efficacy cannotbe obtained without negotiating with the biological
milieu and taking advantage of what it affords. An‘oikological’ approach seems more appropriate, moreheuristic and more promising than the popular missile. Itis based on the view of organism as an oikos that has tobe carefully managed. The dispositions of nanocapsuleshave to be coupled with the affordances of the environ-ment. As it requires dealing with nanoparticles as rela-tional entities (defined by their potential for interactions)rather than as stable substances (defined by intrinsicproperties) this metaphor eventually might well changeresearch priorities in nanotechnology in general.
Keywords Nanomedicine . Pharmacology .Nanorobot .
Magic bullet . Dispositions . Affordances . Efficiency.
Efficacy
Introduction
The use of nanoparticles for delivering drugs on a specificsite is one of the most attractive promises of nanotech-nology today. Targeted drug delivery systems are nano-structures tailored to deliver pharmaco-active moleculesjust where it is needed ([63], p. 135). The major advan-tage of drug vectorization is that it reduces the systemictoxicity of the medicine, thus minimizing side effectswhile improving its efficacy [26]. In addition, this tech-nique allows treating body parts that were once out ofreach from most medicines (e.g.: the brain). Finally, theinnovation is also sought for ‘rescuing’ or ‘repurposing’drugs that were shelved for being too toxic.
Targeted drug delivery systems are flagship productsof nanotechnology. Being less controversial than militaryapplications of nanotechnology, such “nano-weapons”encourage public acceptance of nanotechnology.
Nanoethics (2014) 8:1–17DOI 10.1007/s11569-013-0183-5
B. Bensaude Vincent (*) : S. LoeveCETCOPRA, Paris, Francee-mail: [email protected]
S. Loevee-mail: [email protected]
B. Bensaude Vincent : S. LoeveUniversité Paris 1, Paris, France
B. Bensaude VincentIUF, Paris, France
Reminiscent of the popular image of the ‘magic bullet’,current research projects in nanotechnology for drugdelivery are pervaded by a host of warfare metaphorssuch as ‘therapeutic missiles’, ‘nano bullets’, ‘nano-weapons’, ‘smart bombs’, ‘stealth kill’, and ‘targetedstrike’ without ‘collateral damages’ [6, 12, 31, 40, 43,51, 80, 82, 86, 89, 93]. Such metaphors used in popularjournals and scientific publications have shaped the con-ceptual structure of the research field.
To be sure, this is not specific to nanomedicine. War-faremetaphors have pervadedmedicine and healthcare fora very long time [1, 2, 67, 68]. Their use has beenreinforced by the ‘War on Cancer’, launched by RichardNixon in the 1970s. Focusing on the role of metaphors innanomedicine, this paper pursues previous reflections onthe uses and abuses of such metaphors [74, 75]. However,it goes further in claiming that the values underlying thedominant metaphoric framework are not sustainableenough to design nano-artefacts operating in a complexbiological milieu.
Following a brief presentation of metaphors as concep-tual tools, we contextualize the use of the missile meta-phor against the background of the current pharmaceuticalinnovation crisis in relation to the history of pharmaceu-tical doctrines. Taking a closer look at the devices thathave been designed over the past decades and at currentresearch trends in this field we then argue that the missileor bullet metaphor provides a simplistic view of the com-plex technological systems required to achieve therapeuticefficacy. The military metaphor may suffice for chemists,physicists and engineers who design multi-functional de-vices operating in vitro, as long as they do not operate inthe complex and messy environment of a diseased body.But actions and reactions of biological milieu must beintegrated into the operational scheme of therapeutic de-vices. To go beyond efficiency and achieve therapeuticefficacy in vivo, nanodevices have to be designed not onlyas destructive weapons but as protective shells as well assecret agents conducting negotiations; the biological en-vironment should be conceived as a dense milieu popu-latedwithmultiple and heterogeneous actors rather than asan abstract space traversed by a moving body. Finally, weargue that the use of alternative ‘oikological’ metaphorsencapsulating not just the dispositions of the nano-objectbut also the affordances of the milieu may be useful toimprove the technique. This requires dealing with nano-particles as entities defined by their relations rather than asstable physical or chemical substances thereby calling fora redefinition of research priorities.
This claim is based on a number of research papersdealing with targeted drug delivery both in standardscientific journals and pharmaceutical research journals.Our review of literature has been guided and completedby oral interviews and extensive discussions with threescientists working specifically research field.1
The Performances of Metaphors
It is less a matter of questionning the performances of thetherapeutic applications of nanotechnology than address-ing the relevance of metaphors used in the design ofnanovectors. However, it is not a mere clarification ofwords, disregarding concepts, material practices and eth-ical choices. Richard Rorty claims: ‘It is pictures ratherthan propositions, metaphors rather than statements,which determine most of our philosophical convictions’([88], p. 12).2Metaphors defined as acts of ‘understandingand experiencing one kind of thing in terms of another’,are ordinary cognitive phenomena rather than mere stylis-tic devices ([59], p. 5). As the source domain shapes the‘target domain’, metaphors allow grasping and shapinghitherto-unstructured or not-easily-accessible realities.Metaphors matter. They are powerful ‘catalysts’ in thedynamics of knowledge; they provide insights and gener-ate new meanings and knowledge [62].
Metaphors are also vehicles for the transmission ofmeaning and values. Like viruses, they contaminate andcolonise our minds regardless of well-establishedboundaries such as science versus society. GeorgeLakoff and Mark Johnson emphasize that war meta-phors are ubiquitous in the practices of arguing (we‘defend’ or ‘attack’, ‘gain’ or ‘lose’, ‘demolish’). Theyargue that not just our words, but our common worldwould be quite different had ‘dance’ been, for instance,the source domain of metaphors ([59], pp. 4–5). Meta-phors do literally change the world. They belong to therealm of what John L. Austin called ‘performative ut-terances’ [3]. They are ‘performative’ and not
1 Interviews with Patrick Couvreur (Institut Galien UniversitéParis-Sud), Florence Gazeau (Laboratoire matière et systèmescomplexes, Université Paris Diderot) and Ania Servant(Nanomedicine Laboratory, University College London Schoolof 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.
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‘constative’. More than describing reality, they informand transform it.
Scientific language is not deprived of performativity.Metaphors proliferate in the language of science for thepurpose of communicating science to lay audiences, andthey also circulate inside scientific communities. EvelynFox Keller’s works outline the heuristic power of met-aphors in biology [28–30]. ‘Different metaphors ofmind, nature, and the relation between them, reflectdifferent psychological stances of observer to observed;these, in turn, give rise to different cognitiveperspectives—to different aims, questions, and even todifferent methodological and explanatory preferences’([28], p. 30). She insists that ‘metaphors do far morethan affect our perception of the world. They draw theattention of researchers, guide their activities and mate-rial manipulations’ ([30], p. 290). In technology, meta-phors can even be turned into operational analogies thatmake things work and help superseding obstacles.
What is exactly the descriptive power of the thera-peu t ic miss i l e metaphor ( i t s adequacy) innanomedicine? What about its prescriptive potential:does it shape research practices in this field? This met-aphor suggests that new therapeutics can be framedalong the model of ballistics. The objective is to carryand deliver the drug onto a target in order to optimize its‘launching window’. Precision guidance, efficiencywithout ‘collateral damages’, … the advantages ofnanovectors are listed in terms similar to those used todescribe the performances of missiles or drones in mod-ern warfare. Remarkably, the source domain in turnmakes an extensive use of medical analogies such as‘surgical strikes’, a metaphor used in warfare strategyand communication during the First Gulf War. No mat-ter whether you want to heal people or kill them, nomatter whether your action is good or bad, the ultimatevalues are control and precision.
The Magic Bullet in the Context of Crisisof Pharmaceutical Innovation
The hype surrounding nanotechnology and the claimsthat it brings about a revolution in medicine and phar-macy are based on the awareness of the limitations ofcurrent trends in pharmaceutical research. The franticquest for the miracle molecule that would cure all can-cers following Richard Nixon’s launch of the ‘War onCancer’ in 1971) ended in failure. It is now widely
accepted that the ‘blockbuster model’ is inadequate.Cost soars and the rise of generic drugs are putting anincreasing pressure on big pharmas as their amount ofR&D time and expenditures rise while the output of newtherapeutic molecules decreases [24, 70, 96]. Manyproducts that are tested in clinical trials fail despitetremendous time investments—up to 15 years—and re-source spendings. So hard is the ‘Valley of Death’ forcandidate molecules before reaching the market thatselective reporting of trials is a temptation for pharma-ceutical companies [20, 39].
In the face of this crisis, genomics, genetic engi-neering, nanotechnology and synthetic biology areexpected to reinvigorate a decaying business model[19, 81]. Both personalized medicine and targeteddrug delivery attract big investments from the privateand the public sectors concerned with the sustainabil-ity of the public health system [25]. They search formore ‘rational’ (based on molecular features) andmore ‘reasonable’ (more profit and increased effica-cy) ways of designing pharmaceutical productsthrough more individualized administration of drugs.While in personalized medicine better administrationmeans better prescription,3 in drug targeting it trans-lates as better delivery. Personalized medicine andtarget drug delivery are seen as complementary ratherthan competing strategies [48, 69].4 By adjustingprescription and delivery to individual profiles, well-established medicines may be used to better effect[11]. It is a key argument for stimulating public ad-hesion because it seems to overcome the disadvan-tages and defects of conventional therapeutics. Both
3 Because all individuals are not responding to the same drug,personalized medicine is looking for molecular signatures—socalled ‘biomarkers’—that would allow to direct different catego-ries of patients to more adapted therapies, possibly on the basis ofearly diagnoses (molecular biomarkers are anything that can bedetected and used for measuring the probability of incidence of adisease, its progress, or its treatment’s effects: DNA or RNA singlenucleotide polymorphism, protein, complex of proteins, or chang-es in protein expression).4 Personalized medicine seeks to specify therapy by means ofprofiling and stratification: It sets up distinct categories of patientswith regard to their probability of better responding to this or thattherapy on the basis of tests determining the presence of a bio-marker. It is to form categories of patients fitting with prescriptionsand conversely to adjust prescriptions to categories of patients.Targeted drug delivery, by contrast, starts from a given moleculeand a given target (organ, tissue, cell, organelle or molecularreceptor) and seeks the most fitting nanoscale formulation to carrythe molecule to the target.
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sectors have raised intense mobilization over the pastdecade as a result of a remarkable convergence ofinterests between patients, science, politics and busi-ness. Patients and physicians want to avoid the dam-ages caused by conventional chemotherapy and ra-diotherapy in the treatment of cancers. Pharmaceuti-cal companies want to avoid the rising research costsfor new therapeutic molecules, and public health ser-vices want to avoid the tremendous financial loss dueto the inefficacy of a large proportion of medicalprescriptions. Although big pharmaceutical compa-nies are still hesitant to invest in this field,5 they seetargeted drug delivery as an opportunity to renewtheir patent portfolios.6 On the business side, drugtarget ing is expected to cover 75 % of thenanomedicine market [99]. Therefore hundreds ofresearch laboratories across the globe are currentlybringing together the resources from nanotechnology,advanced polymer and lipid chemistry, physics andmolecular biology in order to find new ways ofvectorizing drugs. Such is the pressure for introduc-ing this new technique in cancer therapeutics thathundreds of candidate products are now in clinicaltrials. It is reported that 27 candidate productshave already been approved by the US Food &Drug Administration in 2012 [78]. Targeted drugdelivery has become a target in itself justifying awarlike mobilization, reinforced by a rhetoricalarsenal of ‘therapeutic missile’, ‘smart bombs’,and the like. As the military metaphors inspire aconvergence of efforts on a common target desig-nated as the enemy, they are self-vindicating. Inusing them, nanotechnologists, physicians, and pa-tients struggling against cancer may feel that theyparticipate in a general mobilisation for an intrin-sically good cause [74].
The Magic Bullet and the Two Culturesof Pharmacology
The climate of crisis in pharmaceutical innovation mayhave intensified the use of warfare metaphors but themetaphors have been around in the twentieth century.Their success testifies to the triumph of the chemicalapproach to medicine, initiated by Paracelsus in thesixteenth century against the older Galenic tradition.7
Paracelsus grounded his therapeutic approach on a the-ory of secrete correspondences or sympathies betweeneach of the seven metals known in his time and thespecific parts of the human body [21, 22]. He assumedthat disease was caused by external foreign agents actingas poisons on a specific area of the body. Diseases wereviewed as localized physical things that the physiciansought to eradicate from the body with the help of anappropriate chemical substance. By contrast, the Galen-ic tradition emphasized the role of fluids and vieweddisease as the result of disturbance in the balance offluids due to an excess of one of the four basic humours.The role of the physician was to restore what we calltoday the body’s homeostasis by prescribing the oppo-site humour. While Galenic medicine dealt with theorganism as a whole and a nexus of relations,Paracelsian therapeutics rests on the affinity ofchemicals with specific tissues. The holistic concept ofdisease characteristic of the Galenic tradition has beenoverthrown by an ontological concept of disease as anens morbi, a material and localized entity.
The idea of eradicating disease with an appropriatemolecule came out of advances in synthetic chemistryand stereochemistry at the turn of the twentieth century[85]. Paul Ehrlich, in particular, paved the way totargeted medicine. As a ‘microbe hunter’, he was oneof the first scientists to use staining techniques to detectparticular cells. While studying the selective action ofaniline dyes on biological tissues, he hypothesized thatcells have specific receptors enabling them to take upspecific molecules. Just as Emil Fischer had venturedthe analogy between lock and key to explain how en-zymes bind with specific substrates, Ehrlich used thehypothesis of chemical affinities—called today ‘mech-anisms of molecular recognition’—to identify toxins
5 Currently, the innovation landscape of nanovectorization ismostly populated with small start-ups selling their patents to bigpharmaceutical companies [77]. They rely on venture capitals andbusiness angels to bear the costs of preclinical development,scaling-up studies, upgrading to legal standards, and phase-I tomid-phase-II trials. Big pharmas cover only end-phase-II andphase III. They adopt a ‘wait-and-see’ strategy ([97]: 4) and refuseto rush head down towards a disruptive technology unless it haspugnaciously proven its safety and efficiency [15].6 It is expected that targeted drug delivery will provide pharma-ceutical industry with new patents thanks to the nanoformulationof established molecules before the end period of their IP rights. Italso allows patenting older medicines that so far could not enter themarket ([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 reallywhat their heirs have made of them. The master narrative built onthe two heroes are still framing pharmacological culture.
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with a selective therapeutic action on specific cells. Hethus tested hundreds of dyes on mice in search for theunique dye that could target the large trypanosomeresponsible for sleeping sickness. In 1910, he obtainedan effective drug against syphilis, Salvarsan. Based onthe molecular recognition between toxin and tissue, hisstrategy inspired the image of ‘magic bullet’, chosen asthe title for a 1940 biographical movie, Dr Ehrlich’sMagic Bullet (Fig. 1).8
So appealing was this popular image that it has beentaken up by drug designers and gradually became a kindof ideal-type driving research efforts [94]. The ‘magicbullet’ model underlies many research strategies thatcame to prevail in twentieth-century pharmaceutical in-dustry. New techniques invented in the 1960s reinforcedthe Paracelsian concept of disease as a local target toshoot. When systems of controlled drug-delivery cameinto use for a number of diseases [45], the ‘magic bullet’became a fashionable motto. Themetaphor almost turnedinto a real thing in the 1970s as pharmaceutical compa-nies began producing monoclonal antibodies by cloninga unique parent cell having some specific action ontumours. It became even more prevalent with the proofsof concept of ‘microspheres’ [57], ‘Nanokapsul’ [53],and ‘Nanopartikel’ [54] that penetrate into specific cellsfor drug, gene or protein delivery, due to Peter Speiserand his team at ETH Zürich [17, 55, 64, 65]. The ‘magicbullet’ is now integrated in more complex systems aimedat materializing the ideal-type of targeted therapeutics.The expectation is to shift from the painstaking drugscreening—testing lots of molecules on all possibletargets—to the direct design of the unique weapon ad-justed to its target.
The pharmaceutical arsenal enriched with such mag-ic bullets is clearly an outcome of the Paracelsian tradi-tion. To what extent does it mark the death of theGalenic approach to diseases? Could target drug deliv-ery be alternatively viewed as a revenge of Galenics, asit has been suggested by Patrick Couvreur, a Belgian
scientist who pioneered the field of targeted drug deliv-ery? [14] Surely, drug delivery just like today’s Galenicpharmacology is concerned with the formulation andadministration of drugs. 9 The delivered substance mat-ters less than the mode of delivery. All efforts are thusaimed at designing new medicinal forms (Galenicforms) rather than new drugs. The goal is less to increasethe efficiency of the therapeutic agent than to enhancethe therapeutic index (the toxic vs. therapeutic doseratio) by increasing the efficacy of delivery.
Are we to assume that targeted drug delivery may beseen as a reconciliation of the two alternative concep-tions of disease and therapeutics? To address this ques-tion, it is necessary to characterize the material practicesof design.
Engineering Therapeutic Devices
Current research on targeted drug delivery differs insubstantial ways from both traditions in that it turns
8 Ehrlich wrote that “If we picture an organism as infected by acertain species of bacterium, it will obviously be easy to effect acure if substances have been discovered which have an exclusiveaffinity for these bacteria and act deleteriously or lethally on thesealone, while at the same time they possess no affinity for thenormal constituents of the body and can therefore have the leastharmful, or other effect on that body. Such substances would thenbe able to exert their full action exclusively on the parasiteharboured within the organism and would represent, so to speak,magic bullets, which seek their target of their own accord” (Ehrlich[27], p. viii).
Fig. 1 Dr Ehrlich’s Magic Bullet, 1940, original motion pictureposter, © 1940 Warner Bros
9 Significantly, twentieth century Galenics refers to the ‘formula-tion’ of drugs, i.e.: making tablets, suppositories, creams or syrups,according to a specific procedure called a ‘formula’ (a medicinalform suitable for administration). Galenics is often despised bymodern pharmacology as being concerned with external form orpackaging instead of active principles, as being technique or evenmarketing, not science—a rather unfair view, since it is Galenicsthat allows the transformation of a mere ‘drug’ into a proper‘medicine’. Galenic pharmacy is indeed indispensable for thestandardisation of doses and posology as well as for thestabilisation and conservation of active substances [87]. Galenicsis the art of taming substances.
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therapeutics into engineering. Indeed, like all therapeu-tic traditions, targeted drug delivery is mainly concernedwith maximizing the efficacy of treatment and reducingharm. As such, however, therapeutics is conceptualizedas an engineering problem that can be anatomized inunit operations.
The technique is divided up in three basic unit oper-ations: loading, addressing, and releasing the activetherapeutic molecule, each operation having specificdesign requirements. This sequence of operations couldapply to the preparation of a missile, and the therapeuticaction is conceived in terms similar to any ballisticproblem.
The first operation—loading (Fig. 2)—requires thedesign of a vehicle (capsule, sphere, micelle, dendrite,shell…) ‘to carry the drug in a controlled manner fromthe site of administration to its therapeutic target’ ([18]:1417). Since the first capsules synthesized in the 1970swith polyacrylamide, polyalkylcyanoacrylate, albumin,or micelles, numerous candidate materials—polymers,liposomes, cyclodextrins and other nanoparticles—havebeen tested as drug vehicles.
There are some specific requirements for the designof a nanocarrier: size (it must not be too big, not toosmall in order to selectively cross barriers); encapsula-tion rate (it must take up a reasonable amount of thera-peutic molecules while polymerizing10); stability (itmust resist bio-erosion); biocompatibility (solubilityand avoidance of unwanted accumulation) and biode-gradability once the capsule’s mission is completed.
Addressing the drug by controlling the movements ofthe carrier along its trajectory is the core of the targetingstrategy. Ballistic metaphors flourish to describe thebattery of techniques that have been developed. Al-though ‘vectorization’ does not explicitly convey a mil-itary image, it connotes the trajectory of a mobilethrough a geometrical space, which is the key conceptof ballistics. The frequent use of the arrow symbol in theiconography of nanovectors reminiscent of the Euclidi-an vectors used in classical physics reinforces the bal-listic connotation. In addition, fighter aircrafts are oftenreferred to as ‘vectors’ in the control rooms of military
operations. In the case of functionalized nanocarrierswith receptor-specific ligands, the ballistic metaphor ofthe ‘missile’ or ‘vector’ is often supplemented with thecybernetic metaphor of the ‘homing device’,11 therebyconverting the old ballistic metaphors into modern(informational) warfare and ‘smart’ weapons. To cap itall, theranostic nanoplatforms guided by ultrasounds ormagnetic fields are designed as kinds of drones: theirdestructive payload can be remotely triggered whiletheir localization can be tracked on a screen.Nanovectors rhyme with Terminators (i.e., robots pro-grammed to kill and to never miss their target). The so-called ‘third-generation nanovectors’ [18] are designedfor ‘active targeting’ thanks to their ‘decoration’ with‘molecular probes’ (antibodies or ligands) devised torecognise the target’s specific receptors (Fig. 3). Thesespecific ligands grafted on the carrier’s coating are oftendubbed ‘homing devices’. They can also feature cell-penetrating peptides or intracellular adhesion moleculesto facilitate the intracellular penetration of the vector[44].
In addition to chemical means of targeting, activetargeting can also be obtained by using physical stimulisuch as X-rays, infrared, ultrasounds, or magnetic fieldproviding guidance (with magnetite embedded in thecarrier). Embedded magnetite adds another interestingfunction to the drug-loaded carrier because it can bedetected by Magnetic Resonance Imaging. In this case,the same nanodevice acts both as a therapeutic tool andan instrument of in vivo detection and imaging—thuscombining therapeutics and diagnostics into one singleoperation, dubbed ‘theranostics’.12 The device is some-what similar to a drone: It is remotely guided while itsposition is followed on a screen. Other detection andimaging compounds include contrast agents, antibodiesemitting fluorescent light when binding with their targetreceptor, or DNA probes activating a fluorophore whenhybridizing with their complementary strand [98].Nanoparticles with embedded iron oxide lining up in a
10 The encapsulation rate is one of the major bottlenecks for thetechnique. Currently, most systems do not exceed a rate of 10% ofactive principles encapsulated on the total amount of nanoparticlessynthesized, which limits both their cost-efficiency and therapeuticindex.
11 Actually, Norbert Wiener’s conceptualization of feedback orretroaction originated in his warfare research on self-guided de-vices during World War II [32].12 Originally coined to refer to a treatment platform combining adiagnostic test setup with a therapy based on the evolution of thetest results [100], theranostic nanomedicine is now defined as ‘anintegrated nanotherapeutic system which can diagnose, delivertargeted therapy and monitor the response to therapy’ ([95],p. 137).
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chain and changing direction under the influence of amagnet provide the most suggestive image of ananorobot. Florence Gazeau, from Université Paris-Diderot, explains: ‘The remote control by the applica-tion of forces works like a robot: It is the mechanicalmanipulation of a biological object’ [37].13
The third operation—the release of the drug on thetargeted site—can be triggered either from inside bycontrolling the stability and degradation time-lapse ofthe capsule, or from outside by various stimuli-responsedevices. All the unique properties of the nanoscale canbe exploited. For instance, pH-sensitive liposomes andnanoparticules such as chitosan will disassemble beforea tumour in an acidic environment; or a carrier made of athermo-sensitive polymer will become porous by appli-cation of hyperthermia on the target and will then releaseits load; a polymer-coated gold nanoparticle will do thesame when irradiated under near-infrared pulsed light,which penetrates deeply into the tissue and causes goldliquefaction [13, 91]; an iron nanoparticle will overheatand cause cancer cell’s necrosis when subjected to a
magnetic field. In the latter case the nanoparticle be-comes the drug: Drug and device merge.14
Each unit operation— loading, addressing,releasing—involved in targeted drug delivery isassigned to a specific device. The combination of thesedevices in a nanoparticle is often called a nanomedicine‘platform’ because of the device’s multi-tasking perfor-mance: imaging (optical, ultrasound or magnetic reso-nance detection), targeting agents (peptides, antibod-ies…), therapeutic tools (chemotherapy, hyperther-mia…), and stimuli-responsive agents that activatethose functions (Fig. 4).
The resulting system is like a ‘mille-feuilles’ of disci-plines comprising of various layers: synthetic chemistry,physics, biochemistry or molecular biology (Fig. 5). Likemost nano-engineering projects the design of nanocapsulesrequires the convergence of various disciplines at thenanoscale. To a certain extent the nanocarriers are crafted
13 Here, ‘robot’ clearly means an enslaved machine-tool, not anindependent automaton. This is not surprising, since, as Nerlichargues [72, 73], the images of nanobots cleaning fats in bloodvessels are recycling the older visual archetypes of shrunk humanstravelling through the body, as shown in the movie The FantasticVoyage. Nanomedicine’s imaginary has replaced shrunk surgeonsand their tools with miniaturized robots. In turn, the focus hasshifted ‘from the “extraordinary” (voyages) to the “ordinary”(medicine), thereby contributing to the normalisation ofnanomedicine and its integration into normal biomilitaristic med-ical 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 theNanoXray™ developed by the French start-up Nanobiotix (http://www.youtube.com/watch?v=kxSX6YJTS2I), in which thenanoparticles amplify the physical mode of action of radiotherapy.NanoXray™ is like a nanoscale extension of the radiotherapy setupinternalized in the patient’s body to relay and locally amplify its effect.This conflation is also visible in the normative framework of regulationunder which the development of NanoXray™ is placed: under thecategory ‘drug’ by the US FDA and under the category ‘medicaldevices’ by the French AFSSAPS. This later regime of regulationwould, if not accelerate, at least facilitate NanoXray™’s entrance in themarket by bypassing the ever-expanding ‘valley of death’ of pharma-ceutical development. As a venture capitalist investing in the start-upput it on one of the Nanobiotix’s site podcasts, ‘I believewe are gettinga biotech care company potential with a medical device time-to-market’ (http://www.nanobiotix.com/about-us/).
Fig. 2 Encapsulation of a drug in a liposome (S. Loeve, original picture)
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like ‘materials by design’, they are then functionalized forperforming specific tasks.
It should be clear by now that the resulting approachto therapeutics belongs neither to the Galenic culture ofpharmacology nor to its Paracelsian rival. In oppositionto the Paracelsian approach, the chemical agent is by nomeans the unique active principle of the medicine. It ispart of a larger technological system combining variousfunctions that all cooperate to the therapeutic action.Conversely, the Galenic formulation becomes so func-tionalized at the nanoscale that it is no longer possible todraw a clear boundary between the excipients and theactive principle [61]. The formulation is an integral partof the therapeutic system.15 Targeted drug delivery sys-tems do not fit in the traditional categories of pharma-cological culture and knowledge. They instantiate atechnoscientific approach dominated by an abstractengineer's view.16 Even the performances that areexpected from them are formulated in the language of
technology assessment (cost/benefit analysis). Each ofthe functions added to the nanoplatform should in-crease the ratio of benefits versus costs and beassessed under this model [10].
From a Model of Efficiency to Therapeutic Efficacy
The missile metaphor is attractive because of the trans-lation of a therapeutic project into an engineering prob-lem with clear end (cure cancer) and means(nanocarriers for the transport and stimuli for the releaseof the medicine). However, is the ballistic metaphorsufficient, is it even necessary? What kind of model isrequired to combine technological efficiency with ther-apeutic efficacy?17
First of all, if the warfare metaphor is to be main-tained, it requires at least more than performing thesequence of unit operations: loading, addressing, releas-ing. To successfully deliver the right dose in the right
15 The nanocarriers obtained by ‘squalenization’ by Couvreur andhis team instantiates the identification of the drug with its Galenicformulation. Squalene, a biological organic compound, can chem-ically bind with the anticancer drug gemcitabin, thus forming anew molecular entity, gemcitabine-squalene, which in turn self-assembles into nanoparticles in water [84].16 On the difference between abstract and concrete engineeringviews in nanotechnology see [5] 79–82).
17 Efficacy is generally defined as the ability to bring about adesired effect, whereas efficiency measures the ratio of beneficialoutput (e.g.: useful fork, economic profit) versus (the amount ofmeans/resources) involved (time, energy, effort, costs…). Thera-peutic efficacy is the main concern in the development process(where it becomes the most important criterion).
Fig. 3 Three generations of nanovectors according to Couvreur and Vauthier [18]. (S. Loeve, original picture)
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place at the right time in the complex environment of aliving organism requires at least ‘smart weapons’ withmultifunctional parts. Consider the first unit, the cap-sule. It has to be designed both as a vehicle and as acontainer for transporting the active principle.While thenano-size facilitates the circulation through the bloodvessels and allows intravenous injections (usually themost dangerous drug administration route for the risk ofembolism), for containing the optimal dose of activeprinciple, the nanocapsule presents the inconvenienceof a low volume for drug loading. Designing the capsuleimplies a trade-off between size and dosing. For a suc-cessful therapeutics, the designer has to find out the
optimal trade-offs afforded by the nanoscale, with re-gard to the kind of effect s/he chooses to prioritize.
In addition, the capsule does not only carry a ‘pay-load’, it also protects the biological milieus from thevirulence of the active principle. Targeted drug deliveryreally took off when doxorubicin has been encapsulatedin biodegradable polyalkylcyanoacrylate nanoparticles[16], lessening the drug’s notorious and often prohibi-tive cardiac toxicity. The container secures the contain-ment of a dangerous material. Its protection is alsocrucial for expanding the spectrum of potential drugsto biological substances. So far peptides, proteins,nucleic acids have been considered as undeliverablebecause they are rapidly cleared and degraded in thebiological milieu. The still uncertain future of genetherapy will thus depend on the ability to protect thefragile drug through its journey. Whether the therapeuticprinciple is a highly toxic substance that needs to beisolated from the vulnerable milieu or a fragile degrad-able biological material that needs a protective contain-er, in both cases, the carrier affords care.
Second, achieving a successful therapy is not simplya matter of guiding a projectile toward a target with thehighest precision and optimal trajectory. The designer ofthe ‘smart bomb’ has to ensure the stability of thevehicle in the messy biological milieu for increasingits residence time in blood vessels. This challenge re-quires astute tricks to deal with obstacles occurring ateach step. The first obstacle is the opsonisation of the
Fig. 4 A nanomedicine platform: an assembly of specific func-tions (S. Loeve, original picture)
Fig. 5 Layered structure of a multifunctional nanoparticles: A ‘mille-feuilles’ of disciplines. (S. Loeve, original picture)
Nanoethics (2014) 8:1–17 9
carrier (the marking of a foreign body alerting the de-fences of the host organism that this exogenous elementhas to be cleared out from the blood vessels). How tonegotiate with this self-defence of the host organ-ism? To face this obstacle the ‘magic bullet’ hadto be disguised or coated. The so-called ‘second-generation nanovectors’ [18] are grafted with asort of hair on the surface of their capsule to makethem invisible to the macrophages along their trajectory.Made of a polymer—most often polyethylene glycol(PEG), because it is FDA approved, cheap andbiodegradable—the coating creates a cloud of hydro-philic chains, which repels for a time the plasma proteinsthat mark the non-self. This process named pegylationprotects the carrier from disintegration by the immunesystem, thus enabling its circulation in the blood for amuch longer period of time. The pegylated particleshave a circulating half-life of 45 h versus a few hoursfor conventional liposomes.
It is thus clear that the missile metaphor is over-simplistic and not sufficient to achieve therapeutic effi-cacy. More importantly, this metaphor conveys the mis-leading image of a kind of navigation system. Unlike ahoming missile, the nanovector is not heading straightfrom the injection site to the target.18 It has a randomand hazardous journey through the blood vessels until itmeets its target and binds to it.19
Finally, the image of a weapon hitting a target is noteven appropriate to describe the release of the drug. Onemajor challenge is that along its journey through theblood vessel, the decorated carrier is modified by themilieu and even redecorated by it, for instance by drag-ging a variety of proteins forming what toxicologistsname the ‘protein corona’. The proteins in the serumform a protective shield, which alters the targeting ca-pabilities of the device [33]. What the tumour cells‘sees’ is not the expected keys that fit in their locks.
They ‘see’ a different and unreadable message [37].Whereas an unambiguous lock-and-key response is ex-pected from the target, the target actually affords aunique viewpoint on the nanoparticles, opening unex-pected perspectives over unforeseen interactions.
Thus the target is by no means a passive site ofimpact. Rather it is a new milieu reconfiguring theparticle’s identity. One major challenge for the successof drug delivery devices is therefore to continuously payattention to the interactions between the technologicaldevice and the milieu.
The description of the nanoplatform as an assem-blage of independent functionalities that can be activat-ed by internal or external stimuli is somewhat mislead-ing. It does not take into account the synergistic orantagonistic effects between the artifact and the milieu,which may alter the devices’ functions and effects. Theimage of a carrier moving straight to hit a specific targetis only an abstract model that may be appropriate toconduct laboratory experiments. While in vitro tests areindispensable for obvious epistemic and ethical reasons,they tend to generate illusions of control and efficiency.They may become counter-productive if they concealthe problems posed by the complex and stochastic be-haviour of the biological milieu. It is thus clear that astrict Paracelsian chemical approach to drug delivery isdoomed to fail in nanomedicine.
To improve the current strategies of drug deliverywith nanocapsules, is it possible to bridge the gap be-tween in vitro and in vivo performances by integratingthe milieu as a third player in the game? While theproblem is generally framed in terms of targeting thedrug-loaded nanovehicle with increased control preci-sion, more efficient and more robust devices relying onthe actions and reactions of the cells are designed.Similar to those were the so-called ‘first-generation’and ‘second-generation’ nanovectors. For instance, the‘second-generation’ nanovectors capitalize on a strata-gem developed by the tumour to capture a part of theblood flow. Whereas in healthy blood vessels endothe-lial cells are bound together by tight junctions,preventing any large particle in the blood from leakingout, in tumours or inflamed tissues, blood vessels do nothave the same sealing ability and are consequently morepermeable20 This increased permeability known as
18 To be sure, military missiles sometimes release munitions with-out homing devices, at random, in the hope that enemy targets willbe affected by statistics. But they don’t have the glamour ofsurgical strikes.19 Even when the drug carrier is equipped with specific antibodies,peptides or ligands, these so-called ‘homing devices’ do not pointonly to a target receptor, but also sometimes to a relay receptorenabling the nanovector to cross a biological barrier. For instance,when decorated with the specific antibody of the transferrin recep-tor, chitosan nanospheres can cross the blood–brain barrier fordelivering biologically peptides to the brain [52]. In this case, atemporary alliance is contracted with a smuggler afforded by aparticular biological milieu.
20 Enhanced Permeability and Retention is the effect of inflamma-tion, which induces the arrival of macrophages and the release ofcytokines increasing the permeability of vessels.
10 Nanoethics (2014) 8:1–17
Enhanced Permeability and Retention effect (EPR) ofthe tumour capillaries allows liposomes or nanoparticlesto slowly permeate the tumour sites (Fig. 6). This ‘non-specific targeting’ (Fig. 3) enables pegylated liposomesto reach tumours sites to deliver drugs while makingchemotherapeutic drugs less toxic for healthy tissues.The doxorubicin-loaded liposomes Doxil® with theirsize of about 100 nm allow administrating a higher doseof doxorubicin while providing the patients with a betterquality of life—(no more nausea, vomiting or hairloss)—although new side effects are also experienced.21
Doxil® totals almost $600 million in annual salesaround the world and will soon lose its patent protection.
New strategies for drug delivery are being envisionedthat take into account the complex and dynamic natureof the biological milieu. In particular the modificationsinduced by the pathology and the treatment in the targetat different space and time scales have to be systemati-cally investigated. The tumor microenvironment is char-acterized by a high structural heterogeneity, multicellu-lar composition, dense extracellular matrix, non-uniform leaky vasculature, continuously evolving inter-stitial pressure and solid stress, hypoxia and involve-ment of immune cells [49, 83]. Multistep strategies arebeing envisioned including a first step to prepare themilieu (normalization of tumor vasculature or of thetumor matrix) and a second step to facilitate drug deliv-ery to the cellular or intracellular target [9, 90, 101].Designing nanoparticles that respond to properties of thetumor microenvironment (for example low pH and par-tial oxygen pressure) is a major trend in the field ofcardiovascular diseases. Targeted drug delivery couldalso be ‘pathology-inspired’, that is, achieved throughendogenous disease-specific mechanical stimuli.22 Here
again the interactions of nanocarriers with the milieu,and more specifically with the diseased area, triggersopportunities of therapeutic activation. Such stratagemsengagingwith the milieu as a partner promise to bemorerobust and widely applicable than the simple molecularrecognition initiated with the model of magic bullet.‘Intelligent design’ [18] of drug delivery could be basedon a better understanding of interaction mechanismsbetween the biological milieu and foreign bodies so asto benefit from them.
The efficiency and efficacy of the military strategy oftargeting and shooting are thus questionable. Even whenit is extended beyond the realm of ballistics to encom-pass smart and fine-tuned devices performing variousfunctions, the missile metaphor is not fully adequate.Twelve years of intensive research did not bring aboutthe promised results. The expected economic benefitsare so disappointing that some experts recommendreconsidering the entire technology in close interactionswith users and regulatory agencies [97].
It is now clear that the exclusive focus on the nano-particle (the vehicle) conceals many complex phenomenaassociated with transport through a living body [58]. Itreduces the spectrum of possibilities by excluding otherpotential perspectives. While the image of a missileprovides insights, it also generates new forms of igno-rance precisely because of its evident simplicity. In par-ticular the offensive rhetoric undermines a subtle fine-tuning between a variety of mechanisms of protection oreven of care. First, the biological tissues are protectedfrom the drug’s toxicity thanks to the container, which isin turn protected from the body’s defences by the coating.As a matter of care, targeted drug delivery requires asense of tact and diplomacy. The so-called ‘missile’ hasto be also a ‘secret agent’ in order to infiltrate into a seriesof biological milieus and manipulate the interactionsbetween various protagonists. Like the Trojan horse, thenanocapsules conceal their operation by adopting thecodes of the infiltrated milieu. The so-called ‘missile’has to negotiate access like a good diplomat. Instead ofsubjecting all obstacles along its path, it has to establishtemporary alliances with various smugglers. Nanovectorsrequire the tricks of a wizard and the special talent ofkaïros. This persona of Ancient Greek mythology, theson of Athena and grand-son of Zeus and Metis, is goodat seizing opportunities. He epitomizes the art of makingdecision in the right place and at the right moment. Thisart consists in seizing what the situation affords forperforming the next step in an action.
21 This is the case of the palmarplantar erythrodysesthesia or‘hand-foot syndrome’. Hands and feet are usually subjected tomechanical pressure and friction, which causes instantaneous di-latation of the endothelial tissue of blood vessels which, similarlyto the EPR effect. Yet this allows the nanocarriers to locally crossthe endothelial wall of healthy tissues. The areas affected becomered, dry, peel, numb or painful, with possible necrosis. This un-wanted leakage of the nanocarrier can be attenuated by modifyingsome everyday activities (avoiding wearing tight clothes, usingtools, jogging, taking hot showers or being exposed to strongsunlight). But for very sensitive patients such an adverse effectunfortunately limits the maximal safe Doxil® dose that can beadministrated as compared with doxorubicin in the same treatmentregime.22 For this purpose, lentil-shaped liposomes were designed torelease their content only under the high shear stress found inconstricted blood vessels [47, 56].
Nanoethics (2014) 8:1–17 11
Towards an Oikological Approach
Since the missile metaphor is neither sufficient nornecessary to account for all the spectrum of astutestratagems required to secure therapeutic efficacy,it seems relevant to open the register of linguisticpractices to alternative metaphors. It is especiallyimportant because, as Bjorn Hofmann convincinglyargued [46], technology plays a leading role inframing medical knowledge. It contributes to shapeour concept of disease, our vision of medical in-tervention on the human body and, last but notleast, our vision of the body. The ballistic meta-phors rely on an abstract view of the body as ablank geometrical space through which a vector ismoving towards a target. By contrast, the emphasison the interaction with the biological milieu con-veys the view of the body as a complex andheterogeneous environment. It consequently bringsto mind a quite different metaphoric framework.
We suggest that drug delivery research could beadvantageously framed in terms of domestic economyor ‘oecology’ (from oikos, ‘house’, the common root forboth ecology and economy). The concern with the man-agement of doses and transportation, which prevails inthe still fashionable military metaphors, would be sup-plemented by an art du ménagement (care). From thisperspective, the designer would have to take care of theinteractions between technological devices and the
milieu where they operate. In the oikological model,the human body is conceived as an oikos populated witha variety of habitants. It is a crowded and uneven terrain,a landscape of ecological niches. In the military frame-work, drug delivery is a strategic game opposing twoplayers—the drug and the target—, whereas in theoikological framework the game involves a varietyof players capable of assuming various roles. Eachof them requires care, protection and tact for theprocess to work. Their local interactions have to beorchestrated from place to place as the drug pursuesits journey inside the body. In the ballistic vision,the therapeutic devices are positioned against thebarriers that stand between the healthy organismand the pathogen target. In the oikological vision,recovering health is to inhabit and tame the sickbody, which is actually a plausible view of cancer[7, 8, 34–36, 66].
To develop an alternative oikological metaphoricframework we have to clarify the mode of existence ofnanomedical devices for targeted therapy. For this pur-pose, the conceptual distinction between dispositions andaffordances may be helpful. It is often claimed thatnanotechnology enables to control and monitor the de-livery process [31, 79]. The objects designed for drugtargeting are usually named ‘nano-devices’—a very wellchosen term, because ‘devices’ (in French ‘dispositifs’)precisely can activate dispositions. To put it in morephilosophical terms, nanoplatforms rely on dispositional
Fig. 6 Addressing tumour tissue through Enhanced Permeability and Retention effect. (S. Loeve, original picture)
12 Nanoethics (2014) 8:1–17
properties when they are designed as missiles.23 Withinthe oikological framework, the unique dispositions arethe physicochemical properties related to the nano-scalethat can be actualized in a specific context. Targeted drugdelivery systems are ‘devices’ precisely because theyactivate dispositions. By contrast the term ‘affordance’refers to the intrinsic capability of an object as well as tothe gift or the service that the said object is able to deliverto its user (for instance thick ice affords skating).24
Whereas a disposition is a latent property inherent to asubstance or based on the laws of nature, affordance isrelational and definitely not substantial. Unlike disposi-tions, affordances are not latent potentials waiting forbeing activated; they do not pre-exist their actualization.Affordances are created within and by the coupling of anagent and a material system; they are rendered possibleby this encounter. Affordances thus blur thepotential/actual dichotomy, as well as the subject/object
divide. Affordances are objective instances because theyare offered by the environment and subjective becausethe offer is generated with regard to a perceptive agent.This concept has recently been used by Rom Harré todevelop a pragmatic account of scientific experimenta-tion which consists of ‘apparatuses/world complexes’affordances [42]. Apparatuses/world complexes affordthings, processes and activities that cannot be constitutednor sustained independently from technical projects.They are hybrid entities—part constructs, partnature—whose causal powers cannot be disentangled.
For instance, in today research programs on drugdelivery, the process of opsonisation of the carrier istreated as an obstacle to be overcome, whereas in an‘oïkologic’ framework, it would be treated as anaffordance of the milieu. All the responses of the biolog-ical milieu to the introduction of a nanocapsule couldserve as models of design. As pointed out by RichardJones, nanotechnology could learn a lot from nature byinvestigating in vivo molecular processes and try to cap-italize on its findings—amajor feature of what Jones dubs‘soft engineering’: ‘The advantage of soft engineering isthat it does not treat the special features of the nanoworldas problems to be overcome, instead it exploits them andindeed relies on them to work at all’ ([50], p. 127).
Changing obstacles into positive principles of workis exactly what the French philosopher GilbertSimondon recommended for the design of ‘concrete’machines as opposed to ‘abstract’ ones [92]. ForSimondon, a ‘concrete engineer’ is one who pays
23 To attribute a dispositional property to a thing amounts to sayingthat if certain conditions are obtained, then that thing will behavein a specific manner or bring about a specific effect. For instance ’anegatively charged particle is one of which it is true that, if broughtinto proximity to another negatively charged particle, it will expe-rience a force of repulsion’ ([41], p. 97).24 The term affordance coined by James J. Gibson in the context ofanimal psychology combines generic material dispositions andspecific intentions and purposes. In Gibson’s ecological theoryof perception, affordances are the possibilities of action that areoffered to an agent by an environment [38]. The concept has alsobeen used in design theory, to express how objects invite andconstrain their users by offering ‘cues for action’ [23, 76].
Table 1 Summary of the contrasts between the two metaphorical frameworks
Representations of Warfare model Oikological model
Body Field of operations visualized on a radar screen.A passive, amorphous transparent and homogeneousspace to go through to reach a target
Multiple oikological niches with various degrees ofcontainement and interactions (e.g. selectivemembrane). An uneven opaque and (over-crowded)milieu
Disease A local entity to be eradicated A relational singularity to be tamed
Health State of well-being resulting from the absence,or the destruction, of disease
Learning process of adaptation to the new conditioncreated by the disease (no return to the biologicalinnocence)
Therapeutic device Missile targeting a pathogenic entity Diplomat negotiating a compromise while takingcare of her homeland
Therapeutic act Strategic game between two actors: the drugand the target
A art du ménagement. Tactic game involving multipleactors to be managed and cared for (and at each stepof the travel) through the body
Nano-object Transparent functionalized entity under controlbecause it is the result of human designand engineering
Relational entity defined by its interactions(for instance protein corona)
Nanoethics (2014) 8:1–17 13
attention to, and takes advantage of, the environmentaffordances. Unlike the abstract engineer, a concreteengineer does not aim to improve the machine’s effi-ciency first, to introduce it ultimately into its workenvironment. But instead, by imagining the machine inits environment and ‘playing the milieu’, the concreteengineer anticipates the effects of its operational effectson the environment, and then tries to integrate them intothe machine’s working principles. A concrete nanoma-chine would work precisely because of—and notdespite—its association with its environment, whichbecomes the machine’s ‘associated milieu’ and not anexternal parameter that engineers have to take into ac-count after designing artefacts. Simondon’s ‘associatedmilieu’ is not something to which a standard, ready-made machine will have to be adjusted. It is an intrinsicaspect of the design of the machine. It means that eachingredient of the complex system is envisaged as arelational entity defined by its interactions with theenvironment rather than a physicochemical entity witha stable identity (Table 1).
Conclusion
Brigitte Nerlich has suggested that Gibson’s notion ofaffordance could help conceptualize metaphors them-selves in ecological terms. ‘An ecological theory of met-aphor would study the “structural coupling” between ametaphor and the environment (…). Over and above itsintrinsic semantics [the metaphor] therefore has a “prag-matic”, dynamic, action-oriented face’ ([71], p. 136). If weassume, with Nerlich, that metaphors do have affordances,depending on their environment or ‘niches’, then we haveto have to acknowledge the ‘magic affordances’ of the‘magic bullet’ and the ‘therapeutic missile’.
First, in the current context of crisis in pharmaceuti-cal industry the missile metaphor affords public confi-dence. The underlying values of control and precisionare more socially acceptable than the view of ananovectors seizing opportunities in the course of arandom journey through the body. Missiles andnanorobots are more reassuring for patients and moreconvincing for investors and industrial companies.
Second, the image of a smart vector penetrating into apassive cell is clearly bound up with masculinity andreflects the gender bias that Fox Keller noticed in theaccounts of molecular biology [28]. The preference foraccounts relying on mechanisms of a stunning
simplicity over others emphasizing complexity is amarked distinction of biotechnology and nanotechnolo-gy and can be related to the prevailing male vision ofhow the body works.
Third, the over-emphasis on the dispositions of nano-particles is also important for patenting purposes. De-spite significant extensions over the past decade, thepatent system still relies on claims of invention, andthus on artefacts. Since drug delivery research is mainlypatent-oriented, it must avoid putting the emphasis onprocesses already performed by nature. Hence theidea that drug delivery research in comparisonwith other fields of nanotechnology only containsa small proportion of biomimetic stances—mostlylimited to the ‘Trojan horse’ stratagems exemplified byviruses and phage.
Despite its advantages, the missile metaphor does notdo full justice to the complexity of the issue. Addressingdrugs to a specific site and releasing the right dose in theright place at the right moment in the complex environ-ment of a living body requires more than a magic bullet.In addition to the various disciplines that converge in allengineering project, nanomedicine requires the engage-ment of the biological milieu as a partner. Therefore, theParacelsian model underlying the ballistic metaphorwhich may be adequate for in vitro demonstrations ofefficiency must be completed by a genuine Galenicmodel of a complex and responsive milieu. The meta-phor of the magic bullet has a limited heuristic powerand brings about disappointing results. Ballistic is notthe relevant technological model because it provides adistorted and biased view of the operations to be per-formed by nanomedical devices. Since they have tonegotiate with the biological milieu and take advantageof what it affords by turning obstacles into facilitators,an alternative metaphoric framework is needed. It thuscomes as no surprise that a number of recent researchtrends in targeted drug delivery focus increasingly onthe milieu thus exploring the potentials of the‘oikological’ approach [60].
Although the broad question of the definition of nano-particles remains far beyond the scope of this paper, it isnot extravagant to suggest that the oikological metaphorcould be extended to other fields of nanotechnology,where it would afford new perspectives. If the relationsbetween nanoparticles and their environment were nolonger treated as side effects and rather as integral partsof their definition and characterization, research priori-ties could be dramatically changed. In today nano-
14 Nanoethics (2014) 8:1–17
initiatives nanotoxicological studies of interactionsbetween nanoparticles and biological tissues orinteractions with the environment are often viewedas a necessary detour for the safe and successfulmass diffusion of nanotechnological productswhereas they could become the hard core of theresearch field. This is just a tentative scenario ofwhat might happen if nanoresearch were to focuson the interactions of nano-objects with theirenvironment.
Acknowledgments We are grateful to Patrick Couvreur, FlorenceGazeau, Ania Servant, Cyril Bussy, and Brigitte Nerlich.
Funding Sources The research for this paper has been conduct-ed by the authors with the help of ANR-project Nano-2EANR-09-NANO-001-02.
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