Advertisement

Clinical and Translational Imaging

, Volume 2, Issue 1, pp 77–87 | Cite as

Nanomedicine technology: current achievements and new trends

  • Elias Fattal
  • Nicolas Tsapis
Review Article

Abstract

Nanomedicines consist of biodegradable or biocompatible submicron-sized colloidal particles encapsulating a drug. Nanomedicine technology has emerged following pioneering work in the 1970s and has given rise to an enormous number of novel delivery systems and applications. Advances in chemistry and engineering have yielded a large panel of biocompatible and biodegradable materials from which nanomedicines can be made. We briefly review the main different types of existing nanomedicines, focusing particularly on those used in the clinic. We then examine the biological barriers nanomedicines must cross to reach their target after intravenous injection, and how these barriers can be overcome. Although mostly conceived for intravenous administration, nanomedicines hold potential for delivery by other routes, such as the oral, ocular and pulmonary routes, which we examine. Finally, we focus on new trends in nanomedicine technology such as stimuli-responsive nanomedicines and the combination of nanomedicines with imaging agents to yield the so-called nanotheranostics.

Keywords

Nanomedicines Drug delivery Enhanced permeation and retention effect Stimuli-responsive Nanotheranostics 

Introduction

Once classically administered, a drug is absorbed and then distributed into the different tissues of the organism, including the target/diseased tissue where it can exert its therapeutic activity. These steps are followed by metabolization, if any, and excretion. In most cases, the percentage of administered drug reaching the target tissue is rather low and side effects can be observed in other tissues. An ideal therapeutic agent, as postulated by Paul Ehrlich in 1906, is one that, like a “magic bullet” (magische Kugel), is able to reach, exclusively, its target. This concept was progressively applied by encapsulating drugs into increasingly complicated drug delivery systems, so as to increase the amount reaching the target. The main idea is to make drug fate dependent on the carrier in which it is encapsulated. Early work focused mainly on microcarriers, but submicronic carriers or nanocarriers offer additional advantages. Indeed, carriers ranging in size from tens of nanometers to a few hundred nanometers can be administered systemically (intravenously) or locally (eye, lungs, nose, etc.). In addition, a small size favors tissue and even intracellular diffusion, opening the way for molecular medicine. Over the past 40 years, investigation of the therapeutic abilities of drug-loaded nanocarriers has become a flourishing research field, leading to the emergence, as nanosized drug delivery systems reached the market, of the term nanomedicine.

Nanomedicines consist of biodegradable and/or biocompatible submicron-sized colloidal particles encapsulating a drug. Recent advances in formulation, material science and physical chemistry have led to the emergence of a broad range of nanomedicines of various sizes, architectures and surface properties and made from very diverse materials. In this short review, we first present the different types of materials from which nanomedicines are made, before focusing on physiological barriers encountered by nanomedicines after their intravenous administration and how these barriers can be overcome. Alternative routes of administration are then presented, followed by new trends in nanomedicine technology: stimuli-responsive systems and nanotheranostics.

Differents types of nanomedicines

The materials used to synthesize or formulate nanomedicines are extremely varied, ranging from organic molecules to inorganic ones. The very first nanomedicines were liposomes [1]. These consist of an aqueous suspension of vesicles, each comprising a bilayer composed of natural or synthetic phospholipids enclosing an internal aqueous compartment (Fig. 1). Their size can be adjusted by different methods such as extrusion or sonication. Drugs can be encapsulated either in the internal aqueous compartment, if they are hydrophilic such as doxorubicin [2] or 5-fluorouracil [3], or inserted within the bilayer if they are hydrophobic or amphiphilic such as amphotericin B [4]. The nature of phospholipids influences not only the encapsulation efficacy but also the in vivo fate of the liposomes after intravenous administration. Indeed, it has been shown that insertion of cholesterol in the bilayer makes it more rigid and, therefore, renders the liposome, if it is small enough (100–200 nm), more stable in the blood stream [5]. The development of liposomal formulations may be limited by the physical stability of the dispersions, drug leakage in the case of small molecules, low activity due to non-specific targeting, clearance by the mononuclear phagocytic system (MPS), and upscaling issues [6].
Fig. 1

Schematic representation of different nanomedicines prepared using either lipids (top) or polymers (bottom) (color figure online)

Other lipid-based nanosystems were considered for drug encapsulation. Lipid nanoemulsions consist of oily liquid lipid droplets, each surrounded by a layer of surfactant (Fig. 1). These droplets can encapsulate hydrophobic drugs in their liquid lipid core, provided the drugs are lipid soluble. They can also entrap amphiphilic molecules such as calixarene [7] or adsorb macromolecules such as antisense oligonucleotides by electrostatic interactions [8]. Their optical transparency, if droplet size is small enough, makes them suitable for topical ocular administration, for instance, to treat dry eye [9]. One disadvantage of nanoemulsions is their poor stability after intravenous injection. In addition, their production requires significant energy input and although low-energy methods exist, they are not yet ready for industrial-scale use. High concentrations of surfactants used to stabilize nanoemulsions may have deleterious effects [10].

Another example of lipid-based nanomedicine is that of solid lipid nanoparticles (SLNs) [11], which combine the advantages of other innovative carrier systems, such as physical stability, protection of incorporated labile drugs from degradation, controlled release, and excellent tolerability, while also overcoming the time and in vivo stability issues of nanoemulsions. SLNs have a solid lipid core (i.e. solid at both room and body temperature) stabilized by a layer of surfactant (Fig. 1). The lipids used are mostly highly purified triglycerides, complex glyceride mixtures or even waxes. Although most SLNs contain hydrophobic drugs, methods based on solvent emulsification–evaporation for the preparation of SLNs loaded with hydrophilic drugs have been introduced [12].

Lipids have also been used, in particular cationic lipids, to formulate nucleic acids (DNA, siRNA, oligonucleotides) to yield nanomedicines [13, 14]. Cationic lipids, by means of electrostatic interactions, are able to condensate nucleic acids and form nano-objects able to protect nucleic acids from degradation and to favor their entrance into cells where they may exert their effect.

Historically, polymers are the second category of materials used to formulate nanomedicines. Polymer nanoparticles were first developed in the mid-1970s by Birrenbach and Speiser [15]. Later on, their application for the design of drug delivery systems became possible thanks to the availability of biodegradable polymers, considered to be suitable for human applications [16]. At that time, research on colloidal drug delivery was focusing only on liposomes but stable systems for clinical applications were lacking. Research has shown that nanoparticles could be more active than liposomes due to their better stability [17], allowing the encapsulation of many drugs (e.g.; antibiotics, cytostatics, nucleic acids). Many different polymers were synthesized and formulated to yield nanomedicines, including polyesters such as poly-dl-lactide, poly(lactide-co-glycolide) or poly-ε-caprolactone, poly-alkyl-cyanoacrylates and even polysaccharides.

These polymers can be formulated into nanospheres or nanocapsules depending on the process used for their preparation. Nanospheres are matrix systems in which the drug is dispersed throughout the whole matrix, whereas nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a single polymer membrane (Fig. 1). Several methods have been developed and can be classified into two main categories according to whether the preparation process requires a polymerization reaction or whether the preparation is achieved directly from a natural macromolecule or a preformed polymer. Nanoparticle preparation methods based on monomer polymerization generally consist of introducing a monomer into the dispersed phase of an emulsion, an inverse microemulsion, or dissolving the monomer in a non-solvent of the polymer. In these systems, polymerization reactions occur in two steps: a nucleation step followed by a growth step. For example, Couvreur et al. [16] developed nanospheres consisting of poly-alkyl-cyanoacrylates by anionic emulsion polymerization of alkylcyanoacrylate dispersed in an acidic aqueous phase. Two methodologies have been proposed for the preparation of nanoparticles from preformed synthetic polymers. The first involves emulsification of non-water-miscible organic solutions of preformed polymers into an aqueous phase containing surfactants, followed by removal of solvents under reduced pressure. Vanderhoff et al. [18] applied this method, named solvent emulsion-evaporation, to poly-dl-lactide. The solvent emulsion–evaporation process can also be modified to yield capsules with an oil or perfluorcarbon core surrounded by a polymer shell [19, 20]. The oil/perfluorcarbon is simply mixed in the organic solvent under the miscibility limit, along with the polymer. The rest of the process remains identical. To encapsulate hydrophilic drugs, a double emulsion (water-in-oil-in-water) is formed with the drug dissolved in the internal aqueous phase (Fig. 1). The second method for obtaining nanospheres from preformed polymers was proposed by Fessi et al. [21] and is called nanoprecipitation which is based on the precipitation of a polymer in solution following the addition of a non-solvent of the polymer. The solvent and the non-solvent of the polymer must be mutually miscible. The progressive addition of the polymer solution to the non-solvent generally leads to the formation of nanospheres around 200 nm in size. Surfactant may be used to promote nanosphere colloidal stability.

Polymeric micelles have also been proposed, deriving from the self-assembly in aqueous phase of amphiphilic copolymers, leading to rather spherical aggregates of a few nanometers in diameter [22]. Given that hydrophobic moieties organize as a core, they can encapsulate hydrophobic drugs thereby modifying their apparent solubility and thus their biodistribution. Amphiphilic copolymers can also form polymersomes, the polymer equivalent of liposomes: a bilayer of amphiphilic copolymer enclosing an internal aqueous compartment [23].

One limitation of classical nanomedicines is their rather low drug-loading capacity, usually below 10 % of the weight of the carrier itself. Researchers have overcome this drawback by synthesizing prodrug molecules that can self-assemble into nanomedicines. One of the best examples of this strategy is the squalenoylation concept. Squalenoylation consists of the formation of chemical linkage between a drug and squalenic acid, a natural precursor of cholesterol synthesis, followed by assembly of the new molecules into nanoparticles by nanoprecipitation [24]. Several molecules have been successfully coupled to squalene resulting in the formation of nanomedicines in which drug loading is increased to around 50 % of the carrier weight. Molecules covalently linked with squalene include gemcitabine [25], paclitaxel [26], siRNA [27] and nucleosides [28]. Studies show a better efficacy of the prodrug nanoassemblies as compared with the free drug for tumor reduction [29].

Materials used are not limited to organic compounds and several groups have optimized inorganic nanomaterials to allow efficient encapsulation of active principles. Although metal organic frameworks (MOFs) were originally developed for hydrogen storage, it has recently been shown that these can be modified to yield nanosized MOFs that encapsulate drugs such as azidothymidine (AZT) or busulfan with rather high drug loadings [30]. Other groups have chemically linked drugs to iron nanoparticles [31].

Crossing physiological barriers

Nanomedicines were mostly designed for intravenous delivery. According to their surface properties, they can be classified into three generations.

After intravenous injection, as non-self particles, nanomedicines are subjected to several physiological processes within the body. Their clearance or destruction may occur even before they are able to reach the targeted disease site. Understanding the role of physiological barriers is of the utmost importance to predict the fate of exogenous nanomedicines and their biodistribution.

Nanomedicines are usually prepared as colloidal suspensions in water or buffer solution. Stability can be assessed in different media to predict what may happen after intravenous administration [32]. In the vascular compartment, in the presence of salts, proteins and enzymes, aggregation, hydrolysis or cleavage of nanomedicines may occur. Nanomedicines below 10 nm are filtered out of the blood stream by rapid clearance through the glomerular capillaries of the kidneys. In the case of nanomedicines up to 500 nm, and depending on their surface properties (charges, hydrophilicity) and their shape, opsonization may occur, followed by macrophage uptake and segregation in organs such as the liver, spleen and bone marrow. Their preferred accumulation in macrophages was exploited to treat hepatocarcinomas with doxorubicin-loaded poly-alkyl-cyanoacrylate nanoparticles [33] or intracellular infections by delivering antibiotics to infected macrophages [34, 35].

Strategies to reduce nanomedicine opsonization led to the emergence of the second generation of nanomedicines characterized by passive targeting of solid tumors. To reduce opsonization, one can consider surface modification with either natural polymers such as polysaccharides (dextran, heparin, chitosan) [36, 37], or synthetic polymers such as polyethylene glycol (PEG) [38] (Fig. 2). The reduction of protein adsorption results in prolonged circulation of the nanomedicine in the blood compartment. Extending the plasmatic half-life increases the likelihood of nanomedicines accumulating passively in solid tumors as a result of the enhanced permeation and retention (EPR) effect, which consists of escape through leaky vasculature and maximal retention due to reduced lymphatic drainage [39] (Fig. 3). The smaller the nanomedicines are, the more efficiently they extravasate through fenestrated neovessels. This property of PEGylated nanomedicine has led to the development of Doxil®/Caelyx®, one of the few nanomedicines used in the clinic. It consists of PEGylated liposomes, also called Stealth® liposomes, encapsulating doxorubicin, and it is used to treat cancer. Liposomal doxorubicin formulations favor a reduction of cardiac toxicity compared to free doxorubicin [40, 41]. Preclinical studies showed an enhanced antitumor activity for the PEGylated liposomal formulations compared with the free form [42, 43]. Clinical studies in patients receiving either PEGylated liposomal doxorubicin or equivalent doses of free drug have shown an up to 16-fold increase in doxorubicin levels in the tumor when using the liposomal formulation [2].
Fig. 2

Schematic representation of the generation of the different liposomes: plain, PEGylated and targeted (color figure online)

Fig. 3

Schematic representation of ideal tumor passive targeting by long-circulating nanomedicines via the enhanced permeation and retention (EPR) effect (color figure online)

Passive targeting of tumors remains limited since the proportion of nanomedicines reaching the tumor site is usually below 10 % of the injected dose [44]. Moreover, as PEGylation reduces plasma protein adsorption, uptake by the reticuloendothelial system is also decreased. In addition, the degree of tumor vascularization and the porosity of the vessels depend on the tumor type and stage of development [45]. Finally, although observed in the clinic, the EPR effect seems to be limited to certain patients [46] and other strategies should be considered to increase nanomedicine accumulation in solid tumors. In addition, it has been reported in several animals that intravenous injections of PEGylated liposomes may trigger an immune response leading to rapid clearance of PEGylated liposomes after a second injection [47]. Research is, therefore, focused on investigating several biopolymers such as polysaccharides to replace PEG in stealth formulations [14, 48].

The third generation of nanomedicines relies on active targeting. Active targeting overcomes the above-mentioned limitations by specifically attracting and/or binding nanomedicines to malignant tissues to increase local concentration. Active targeting can be obtained by applying an external force such as a magnetic field. Several authors explored the feasibility of using an external gradient magnetic field for solid tumor targeting with liposomes loaded with superparamagnetic iron oxide (SPIO) nanoparticles [49]. The magnet is usually placed over subcutaneously implanted tumors, with the magnetic field leading to enhanced accumulation of the nanomedicine in the tumors as compared with the EPR effect. This targeting strategy, however, remains difficult to translate to the clinic due to the need to implant a magnet near the tumor site.

Alternatively, there is the chemical approach of active targeting by decorating the nanomedicine surface with targeting ligands to promote receptor recognition (Fig. 2). Different ligands can be used: antibodies [50], peptides [51], proteins [52], aptamers [53] or small molecules such as folic acid [54]. Active targeting helps to avoid or reduce non-specific binding compared to ligand-receptor interactions. Usually a spacer is needed between the nanomedicine surface and the ligand to promote flexibility and accessibility. For this reason most groups attach the ligand at the extremity of the polymer coating the particle to protect it from opsonization. Active targeting allows increased cellular uptake of nanomedicines due to enhanced receptor-mediated endocytosis [55]. Active targeting is often based on a probabilistic hypothesis, namely that biomarkers such as integrins are overexpressed by endothelial cells on neovessels or epithelial cells. Jokerst et al. [56] considered that the differential of expression, between targeted and non-targeted tissues, of 2–10 was sufficient to ensure active targeting. Nevertheless, healthy tissues may be affected. The expression level of the biomarkers also varies with the genetic pool of the patient and the stage of the disease, therefore affecting the response to targeted nanomedicines. Instead of overexpressed receptors, exclusive receptors for malignant cells should, when possible, be considered. Glypican (GPC), which is absent in normal adult tissue but highly expressed (80 %) in hepatocellular carcinoma is a good example of such a strategy: Park et al. [57] highlighted the specific uptake by Hep G2 cancer cells using PEGylated particles coated with anti-GPC3 antibody.

Beyond the intravenous route

Although nanomedicines are mainly designed for intravenous administration, many other routes of administration are being considered, such as the oral route, the pulmonary route and the ocular route. Of these, the oral route is the one usually preferred by the pharmaceutical industry for its ease of application. Indeed, nanomedicines can protect labile drugs from the degradation induced by the acidic gastric pH. Insulin falls into this category. Although many nanomedicines encapsulating insulin for oral delivery have been developed and have shown promising results in animal models, none of them has yet reached the market, probably due to the narrow therapeutic window. Conversely, nanomedicine formulations may also protect the gastrointestinal tract from toxic or irritant drugs [58]. Some research has focused on the use of bioadhesive polymers for nanomedicine surface modification, the idea being to extend the residence time in the intestine and thereby favor drug absorption [59]. Bioadhesive polymers such as chitosan or thiolated chitosan are typical examples of this approach: their presence on the nanoparticle surface clearly enhanced the mucoadhesion behavior thanks to noncovalent interactions (ionic interactions and hydrogen bonds) with mucus chains. In addition, the presence of thiol groups, forming covalent bonds with the cysteine residues of the mucus glycoproteins, increased the mucoadhesion capacity [60].

Nanomedicines have also been developed for pulmonary delivery, either local delivery or systemic. Pulmonary delivery of nanomedicines, designed to target the highly vascularized alveoli, is a suitable alternative to the parenteral route since it allows the administration of fragile and poorly absorbed molecules [61, 62]. Nanoparticles are highly bioavailable after lung administration since they are well retained in situ and weakly taken up by alveolar macrophages, provided their diameter is below 250 nm [63]. Recent studies have demonstrated the impressive potential of biodegradable nanoparticles for the lung delivery of salbutamol [64]. Nanomedicine can be delivered to the lungs as an aqueous suspension by liquid nebulization [64] or as dry powders encapsulated into Trojan particles [65, 66] to be efficiently deposited deep in the lungs. Sung et al. [66] demonstrated that lung delivery of Trojan particles containing rifampicin allowed controlled release of this antitubercular drug and increased its bioavailability.

Nanomedicines have also proven their efficacy for ocular delivery by topical administration. Several nanomedicines with bioadhesive properties were developed to extend the residence time of the drug at the surface of the eye. In particular, cationic nanoemulsions developed by Novagali Pharma were successfully used for the treatment of the dry eye syndrome [9]. Intraocular injections of nanomedicines were also considered to target the posterior segment of the eye which, because of the hemato-aqueous and hemato-retinian barriers, is difficult to reach both by topical administration and by intravenous administration. For example, encapsulation of vasointestinal peptide into liposomes prevented its rapid degradation after intravitreal injection and extended its ability to downregulate uveitis for about 15 days [67].

Stimuli-responsive nanomedicines

Traditional nanomedicines usually release their drug content by passive diffusion or by degradation of the material forming the nanomedicine (e.g. hydrolysis in the case of polyester nanoparticles). Recently, however, there have appeared stimuli-responsive nanomedicines, able to release their drug payload in a spatial, temporal, and dose-controlled fashion. The release process is complicated since it requires the use of biocompatible materials able to undergo a specific conformational change in response to the required stimulus or to take advantage of the properties of inorganic or organic materials when a specific physical stimulus is applied. Stimuli allowing control of drug release can be exogenous such as temperature, magnetic field, ultrasound waves, light or electric pulses, or endogenous such as pH, intracellular enzymes or redox gradients.

The concept of stimuli-responsive drug delivery was first proposed in the late 1970s using thermo-sensitive liposomes for the local release of drugs via hyperthermia [68]. The most frequently used stimulus for triggering drug release is temperature. Thermosensitive nanomedicines are designed to retain their drug load at body temperature (~37 °C) and specifically deliver the drug upon a slight temperature increase (~40–42 °C). Among the thermosensitive systems, one can cite polymeric micelles or nanoparticles based on poly(N-isopropyl acrylamide) (PNIPAM) which have a lower critical solution temperature [69]. Thermosensitive liposomes are also commonly based on fine-tuning of the lipid composition so that they exhibit a phase transition and conformational changes in the required temperature range. The temperature increase can be obtained using radiofrequency oscillations of a magnetic field or focused ultrasound waves. Doxorubicin-loaded thermosensitive liposomes (ThermoDox®, Celsion Corporation) are a typical example of thermosensitive nanomedicine currently being investigated clinically for different cancer treatments [70]. Perfluorocarbon nanoemulsions loaded with paclitaxel showed a substantial tumor regression and suppression of metastases upon ultrasound application [71]. Endogenous stimuli can also be exploited. For example, Castelleto et al. [72] designed a micellar carrier covalently linked to a drug moiety, whose release was induced by hydrolytic cleavage due to chymotrypsin in the extracellular enzymatic pool and acidic conditions of the tumor microenvironment.

Nanotheranostics

One of the new trends in drug delivery concerns the association of a nanomedicine with a contrast agent to yield nanotheranostic systems allowing both imaging and treatment. The term theranostic, deriving from the words therapy and diagnostics, was first used in 2002. Nanotheranostic systems are designed to image nanocarrier biodistribution, to survey the extent of disease, to deliver treatment and to monitor in real time its mechanism of action and its efficacy [73]. In brief, nanotheranostic systems make it possible to “administer the right drug to the right patient at the right moment” [74]. The carrier should provide an optimal biodistribution and should deliver two payloads: the imaging probe (metallic nanoparticles, quantum dots, fluorophores, etc.) and the bioactive molecule (peptide, protein, nucleic acid or chemotherapeutic drug). The numerous possible combinations of these three elements, their synthesis and their features have already been widely reviewed [75, 76].

Magnetic resonance imaging (MRI) is often chosen as the imaging modality since it provides good resolution and can cover most organs, including the brain. In addition, many MRI contrast agents have been developed that can easily be co-encapsulated into nanomedicines: Gd chelates, superparamagnetic iron oxides (SPIOs), ultrasmall superparamagnetic iron oxides (USPIOs) [77], perfluorocarbons (Fig. 4) [44, 78]. Viglianti et al. performed a meticulous analysis of the release of doxorubicin from liposomes, co-encapsulated with manganese as the MRI contrast agent. They linearly correlated the increase of longitudinal relaxivity (r1) by MR spectroscopy with the doxorubicin local concentrations in the tumor, by comparing HPLC and histological measurements. This method is a promising approach for imaging drug efficacy and real-time evaluation of chemotherapeutic protocols [79]. Langereis and Grüll monitored, by MRI, the controlled release of drug from a temperature-sensitive liposome with commutative imaging capabilities. The chemical exchange saturation transfer (CEST) signal was replaced by the 19F MRI signal upon reaching the melting temperature of the lipid membrane, following the application of high-intensity focused ultrasound and was correlated with the drug release 80, 81].
Fig. 4

19F MR image superimposed with anatomical 1H MR image of a tail-head longitudinal cross section of a mouse 7 h after intravenous injection of PLGA-PEG nanocapsules of perlfluorooctyl bromide for a tumor of 720 mm3 (white dotted circles). Figures adapted from Diou et al. [44] (color figure online)

Although ultrasound imaging allows real-time imaging, ultrasound contrast agents consist mostly of gas microbubbles that, even when associated with a drug moiety, are not, strictly speaking, nanomedicines. However, perfluorocarbon nanoemulsions were designed to become gaseous when insonified, as a result of the combined effects of local increased acoustic pressure and temperature. This phenomenon is called acoustic droplet vaporization (ADV). A droplet to bubble conversion, followed by cavitation, inducing the release of thrombin was observed by Fabiilli et al. [82].

Optical imaging was also considered as a visualization modality in nanotheranostics, but the strong scattering properties of soft tissues in the visible region of the light spectrum (<700 nm) limit its application. However, scattering decreases at longer wavelengths in the near-infrared (NIR) region (700–900 nm), often called “biological window” for optical imaging and many fluorophores were designed accordingly [76]. The organic NIR dye Cy5.5 was used by Kim et al. to label paclitaxel-loaded chitosan-based nanomedicines. In vivo, NIR fluorescence clearly allowed tumor delineation and signal intensity was found to be correlated with nanomedicine concentration. Optical imaging has also made it possible both to follow nanomedicine biodistribution and to monitor non-invasively tumor growth rate in response to treatment (Fig. 5) [83]. Optical NIR probes other than organic dyes, such as gold nanoparticles or quantum dots, can also be loaded into nanomedicines. Nevertheless, since penetration depth of NIR light in tissue is less than 1 cm, the observed tissues must be located close to the radiation source. At present, the clinical use of optical imaging remains limited [76].
Fig. 5

a In vivo imaging of Cy5.5-labeled chitosan-based nanoparticles (CNPs) in tumor-bearing mice. b The pectoral tumor was positive for tumor cells, as confirmed by H&E staining. Fluorescence microscopic images show the CD-31-positive angiogenic vessels (yellow) and DAPI-stained tumor cells (blue). Intravenously injected, Cy5.5-labeled CNPs were visualized in tumor tissues (red). c Time-dependent tumor targeting specificity of free Cy5.5, Cy5.5-labeled polymers, and Cy5.5-labeled CNPs, all with equimolar amounts of Cy5.5 (0.16 μmol). d Tumor-to-background (muscle) ratio as a function of time after administration of Cy5.5, Cy5.5-labeled polymers, and Cy5.5-labeled CNPs. All data represent mean ± SE. Adapted from Kim et al. [83]. (color figure online)

Conclusion

In the wake of pioneering work in the seventies, the imagination and creativity of pharmacists, chemists and engineers has led to the development of thousands of nanomedicines in the endeavor to solve issues such as drug toxicity, poor bioavailability, poor stability and deleterious side effects. Nanomedicines are made from organic and inorganic materials and their size, shape and surface chemistry may be adjusted for specific applications. Although most nanomedicines were initially intended for intravenous delivery, oral, ocular or pulmonary administration may be considered and nanomedicine properties should be tuned accordingly. The new avenues of stimuli-responsive nanomedicines and nanotheranostics seem particularly interesting and remain to be fully explored. In particular, nanotheranostics could be designed to specifically interact with malignant cells, image them, trigger a therapeutic response and monitor it in real time. Overall, nanomedicines will be upgraded from preclinical research to clinical application if the toxicity issues are better predicted and the scale-up and engineering of these complex structures prove profitable.

Notes

Acknowledgments

The authors acknowledge financial support from ANR (Investissements d’Avenir, Nanobiotechnologies, ANR-10-NANO-06). Our laboratory is a member of the Laboratory of Excellence LERMIT supported by a grant from ANR (ANR-10-LABX-33).

Conflict of interest

Elias Fattal and Nicolas Tsapis have had collaborations funded by SERVIER Technologie, Novagali Pharma, Guerbet, Da Volterra.

Animal and human studies

All institutional and national guidelines for the care and use of laboratory animals were followed. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for their inclusion in the study.

References

  1. 1.
    Gregoriadis G, Ryman BE (1971) Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases. Biochem J 124(5):58PPubMedCentralPubMedGoogle Scholar
  2. 2.
    Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4):987–992PubMedGoogle Scholar
  3. 3.
    Joondeph BC, Peyman GA, Khoobehi B, Yue BY (1988) Liposome-encapsulated 5-fluorouracil in the treatment of proliferative vitreoretinopathy. Ophthalmic Surg 19(4):252–256PubMedGoogle Scholar
  4. 4.
    Lopezberestein G, Mehta R, Hopfer RL, Mills K, Kasi L, Mehta K, Fainstein V, Luna M, Hersh EM, Juliano R (1983) Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin-B. J Infect Dis 147(5):939–945CrossRefGoogle Scholar
  5. 5.
    Oku N, Namba Y (1994) Long-circulating liposomes. Crit Rev Ther Drug Carrier Syst 11(4):231–270PubMedGoogle Scholar
  6. 6.
    Gregoriadis G (ed) (1988) Liposomes as drug carriers: trends and progress. Wiley, ChichesterGoogle Scholar
  7. 7.
    Spagnul A, Bouvier-Capely C, Phan G, Rebiere F, Fattal E (2010) Calixarene-entrapped nanoemulsion for uranium extraction from contaminated solutions. J Pharm Sci 99(3):1375–1383. doi: 10.1002/Jps.21932 PubMedCrossRefGoogle Scholar
  8. 8.
    Bruxel F, Cojean S, Bochot A, Teixeira H, Bories C, Loiseau PM, Fattal E (2011) Cationic nanoemulsion as a delivery system for oligonucleotides targeting malarial topoisomerase II. Int J Pharmaceut 416(2):402–409. doi: 10.1016/j.ijpharm.2011.01.048 CrossRefGoogle Scholar
  9. 9.
    Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS (2012) Successfully improving ocular drug delivery using the cationic nanoemulsion, novasorb. J Drug Deliv 2012:604204. doi: 10.1155/2012/604204 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Gutierrez JM, Gonzalez C, Maestro A, Sole I, Pey CM, Nolla J (2008) Nano-emulsions: new applications and optimization of their preparation. Curr Opin Colloid Interface Sci 13(4):245–251. doi: 10.1016/j.cocis.2008.01.005 CrossRefGoogle Scholar
  11. 11.
    Wissing SA, Kayser O, Müller RH (2004) Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 56(9):1257–1272. doi: 10.1016/j.addr.2003.12.002 PubMedCrossRefGoogle Scholar
  12. 12.
    Cortesi R, Esposito E, Luca G, Nastruzzi C (2002) Production of lipospheres as carriers for bioactive compounds. Biomaterials 23(11):2283–2294. doi: 10.1016/S0142-9612(01)00362-3 PubMedCrossRefGoogle Scholar
  13. 13.
    Fattal E, Couvreur P, Dubernet C (2004) “Smart” delivery of antisense oligonucleotides by anionic pH-sensitive liposomes. Adv Drug Deliv Rev 56(7):931–946. doi: 10.1016/j.addr.2003.10.037 PubMedCrossRefGoogle Scholar
  14. 14.
    Dufaÿ Wojcicki A, Hillaireau H, Nascimento TL, Arpicco S, Taverna M, Ribes S, Bourge M, Nicolas V, Bochot A, Vauthier C, Tsapis N, Fattal E (2012) Hyaluronic acid-bearing lipoplexes: physico-chemical characterization and in vitro targeting of the CD44 receptor. J Control Release 162(3):545–552. doi: 10.1016/j.jconrel.2012.07.015 PubMedCrossRefGoogle Scholar
  15. 15.
    Birrenbach G, Speiser PP (1976) Polymerized micelles and their use as adjuvants in immunology. J Pharm Sci 65(12):1763–1766PubMedCrossRefGoogle Scholar
  16. 16.
    Couvreur P, Kante B, Roland M, Guiot P, Bauduin P, Speiser P (1979) Polycyanoacrylate nanocapsules as potential lysosomotropic carriers: preparation, morphological and sorptive properties. J Pharm Pharmacol 31(5):331–332PubMedCrossRefGoogle Scholar
  17. 17.
    Fattal E, Rojas J, Roblottreupel L, Andremont A, Couvreur P (1991) Ampicillin-loaded liposomes and nanoparticles: comparison of drug loading, drug release and in vitro antimicrobial activity. J Microencapsul 8(1):29–36. doi: 10.3109/02652049109021855 PubMedCrossRefGoogle Scholar
  18. 18.
    Vanderhoff J, El Aasser M, Ugelstad J (1979) Polymer emulsification process. United States Patent 4,177,177Google Scholar
  19. 19.
    Losa C, Marchalheussler L, Orallo F, Jato JLV, Alonso MJ (1993) Design of new formulations for topical ocular administration - polymeric nanocapsules containing metipranolol. Pharm Res 10(1):80–87. doi: 10.1023/A:1018977130559 PubMedCrossRefGoogle Scholar
  20. 20.
    Pisani E, Tsapis N, Paris J, Nicolas V, Cattel L, Fattal E (2006) Polymeric nano/microcapsules of liquid perfluorocarbons for ultrasonic imaging: physical characterization. Langmuir 22(9):4397–4402. doi: 10.1021/La0601455 PubMedCrossRefGoogle Scholar
  21. 21.
    Fessi H, Devissaguet J, Puisieux F, Thies C (1991) Process for the preparaton of dispersible colloidal systems of a substance in the form of nanocapsules. United States Patent 5,049,322Google Scholar
  22. 22.
    Jones MC, Leroux JC (1999) Polymeric micelles—a new generation of colloidal drug carriers. Eur J Pharm Biopharm 48(2):101–111. doi: 10.1016/s0939-6411(99)00039-9 PubMedCrossRefGoogle Scholar
  23. 23.
    Lee JS, Feijen J (2012) Polymersomes for drug delivery: design, formation and characterization. J Control Release 161(2):473–483. doi: 10.1016/j.jconrel.2011.10.005 PubMedCrossRefGoogle Scholar
  24. 24.
    Desmaele D, Gref R, Couvreur P (2012) Squalenoylation: a generic platform for nanoparticular drug delivery. J Control Release 161(2):609–618. doi: 10.1016/j.jconrel.2011.07.038 PubMedCrossRefGoogle Scholar
  25. 25.
    Couvreur P, Stella B, Reddy LH, Hillaireau H, Dubernet C, Desmaele D, Lepetre-Mouelhi S, Rocco F, Dereuddre-Bosquet N, Clayette P, Rosilio V, Marsaud V, Renoir JM, Cattel L (2006) Squalenoyl nanomedicines as potential therapeutics. Nano Lett 6(11):2544–2548. doi: 10.1021/Nl061942q PubMedCrossRefGoogle Scholar
  26. 26.
    Caron J, Maksimenko A, Wack S, Lepeltier E, Bourgaux C, Morvan E, Leblanc K, Couvreur P, Desmaele D (2013) Improving the antitumor activity of squalenoyl-paclitaxel conjugate nanoassemblies by manipulating the linker between paclitaxel and squalene. Adv Healthc Mater 2(1):172–185. doi: 10.1002/adhm.201200099 PubMedCrossRefGoogle Scholar
  27. 27.
    Raouane M, Desmaele D, Gilbert-Sirieix M, Gueutin C, Zouhiri F, Bourgaux C, Lepeltier E, Gref R, Ben Salah R, Clayman G, Massaad-Massade L, Couvreur P (2011) Synthesis, characterization, and in vivo delivery of siRNA-squalene nanoparticles targeting fusion oncogene in papillary thyroid carcinoma. J Med Chem 54(12):4067–4076. doi: 10.1021/Jm2000272 PubMedCrossRefGoogle Scholar
  28. 28.
    Hillaireau H, Dereuddre-Bosquet N, Skanji R, Bekkara-Aounallah F, Caron J, Lepetre S, Argote S, Bauduin L, Yousfi R, Rogez-Kreuz C, Desmaele D, Rousseau B, Gref R, Andrieux K, Clayette P, Couvreur P (2013) Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies. Biomaterials 34(20):4831–4838. doi: 10.1016/j.biomaterials.2013.03.022 PubMedCrossRefGoogle Scholar
  29. 29.
    Reddy LH, Renoir JM, Marsaud V, Lepetre-Mouelhi S, Desmaele D, Couvreur P (2009) Anticancer efficacy of squalenoyl gemcitabine nanomedicine on 60 human tumor cell panel and on experimental tumor. Mol Pharm 6(5):1526–1535. doi: 10.1021/Mp900099e PubMedCrossRefGoogle Scholar
  30. 30.
    Horcajada P, Chalati T, Serre C, Gillet B, Sebrie C, Baati T, Eubank JF, Heurtaux D, Clayette P, Kreuz C, Chang JS, Hwang YK, Marsaud V, Bories PN, Cynober L, Gil S, Ferey G, Couvreur P, Gref R (2010) Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat Mater 9(2):172–178. doi: 10.1038/nmat2608 PubMedCrossRefGoogle Scholar
  31. 31.
    Georgelin T, Bombard S, Siaugue JM, Cabuil V (2010) Nanoparticle-mediated delivery of bleomycin. Angew Chem Int Ed Engl 49(47):8897–8901. doi: 10.1002/anie.201003316 PubMedCrossRefGoogle Scholar
  32. 32.
    Fang C, Bhattarai N, Sun C, Zhang M (2009) Functionalized nanoparticles with long-term stability in biological media. Small 5(14):1637–1641. doi: 10.1002/smll.200801647 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Barraud L, Merle P, Soma E, Lefrancois L, Guerret S, Chevallier M, Dubernet C, Couvreur P, Trepo C, Vitvitski L (2005) Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo. J Hepatol 42(5):736–743. doi: 10.1016/j.jhep.2004.12.035 PubMedCrossRefGoogle Scholar
  34. 34.
    Fattal E, Rojas J, Youssef M, Couvreur P, Andremont A (1991) Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis. Antimicrob Agents Chemother 35(4):770–772PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Semiramoth N, Di Meo C, Zouhiri F, Said-Hassane F, Valetti S, Gorges R, Nicolas V, Poupaert JH, Chollet-Martin S, Desmaele D, Gref R, Couvreur P (2012) Self-assembled squalenoylated penicillin bioconjugates: an original approach for the treatment of intracellular infections. ACS Nano 6(5):3820–3831. doi: 10.1021/Nn204928v PubMedCrossRefGoogle Scholar
  36. 36.
    Alhareth K, Vauthier C, Bourasset F, Gueutin C, Ponchel G, Moussa F (2012) Conformation of surface-decorating dextran chains affects the pharmacokinetics and biodistribution of doxorubicin-loaded nanoparticles. Eur J Pharm Biopharm 81(2):453–457. doi: 10.1016/j.ejpb.2012.03.009 PubMedCrossRefGoogle Scholar
  37. 37.
    Amoozgar Z, Park J, Lin Q, Yeo Y (2012) Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor-specific drug delivery. Mol Pharm 9(5):1262–1270. doi: 10.1021/mp2005615 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Jokerst JV, Lobovkina T, Zare RN, Gambhir SS (2011) Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond) 6(4):715–728. doi: 10.2217/nnm.11.19 CrossRefGoogle Scholar
  39. 39.
    Du W, Xu Z, Nystrom AM, Zhang K, Leonard JR, Wooley KL (2008) 19F- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic delivery. Bioconjug Chem 19(12):2492–2498. doi: 10.1021/bc800396h PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin : review of animal and human studies. Clin Pharmacokinet 42(5):419–436. doi: 10.2165/00003088-200342050-00002 PubMedCrossRefGoogle Scholar
  41. 41.
    Abraham SA, Waterhouse DN, Mayer LD, Cullis PR, Madden TD, Bally MB (2005) The liposomal formulation of doxorubicin. Methods Enzymol 391:71–97PubMedCrossRefGoogle Scholar
  42. 42.
    Gabizon AA (1992) Selective Tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res 52(4):891–896PubMedGoogle Scholar
  43. 43.
    Drummond DC, Meyer O, Hong KL, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51(4):691–743PubMedGoogle Scholar
  44. 44.
    Diou O, Tsapis N, Giraudeau C, Valette J, Gueutin C, Bourasset F, Zanna S, Vauthier C, Fattal E (2012) Long-circulating perfluorooctyl bromide nanocapsules for tumor imaging by (FMRI)-F-19. Biomaterials 33(22):5593–5602. doi: 10.1016/j.biomaterials.2012.04.037 PubMedCrossRefGoogle Scholar
  45. 45.
    Bae KH, Chung HJ, Park TG (2011) Nanomaterials for cancer therapy and imaging. Mol Cells 31(4):295–302. doi: 10.1007/s10059-011-0051-5 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Crommelin DJA, Florence AT (2013) Towards more effective advanced drug delivery systems. Int J Pharm 454(1):496–511. doi: 10.1016/j.ijpharm.2013.02.020 PubMedCrossRefGoogle Scholar
  47. 47.
    Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, Kiwada H (2006) Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release 112(1):15–25. doi: 10.1016/j.jconrel.2006.01.005 PubMedCrossRefGoogle Scholar
  48. 48.
    Bertholon I, Vauthier C, Labarre D (2006) Complement activation by core-shell poly(isobutylcyanoacrylate)-polysaccharide nanoparticles: influences of surface morphology, length, and type of polysaccharide. Pharm Res 23(6):1313–1323. doi: 10.1007/s11095-006-0069-0 PubMedCrossRefGoogle Scholar
  49. 49.
    Fortin-Ripoche JP, Martina MS, Gazeau F, Menager C, Wilhelm C, Bacri JC, Lesieur S, Clement O (2006) Magnetic targeting of magnetoliposomes to solid tumors with MR imaging monitoring in mice: feasibility. Radiology 239(2):415–424. doi: 10.1148/radiol.2392042110 PubMedCrossRefGoogle Scholar
  50. 50.
    Koshkaryev A, Sawant R, Deshpande M, Torchilin V (2013) Immunoconjugates and long circulating systems: origins, current state of the art and future directions. Adv Drug Deliv Rev 65(1):24–35. doi: 10.1016/j.addr.2012.08.009 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Kumar M, Yigit M, Dai G, Moore A, Medarova Z (2010) Image-guided breast tumor therapy using a small interfering RNA nanodrug. Cancer Res 70(19):7553–7561. doi: 10.1158/0008-5472.CAN-10-2070 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci USA 104(39):15549–15554 (pii: 0707461104)PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Wang AZ, Bagalkot V, Vasilliou CC, Gu F, Alexis F, Zhang L, Shaikh M, Yuet K, Cima MJ, Langer R, Kantoff PW, Bander NH, Jon S, Farokhzad OC (2008) Superparamagnetic iron oxide nanoparticle-aptamer bioconjugates for combined prostate cancer imaging and therapy. ChemMedChem 3(9):1311–1315. doi: 10.1002/cmdc.200800091 PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Yang X, Grailer JJ, Rowland IJ, Javadi A, Hurley SA, Steeber DA, Gong S (2010) Multifunctional SPIO/DOX-loaded wormlike polymer vesicles for cancer therapy and MR imaging. Biomaterials 31(34):9065–9073 (pii: S0142-9612(10)01077-X)PubMedCrossRefGoogle Scholar
  55. 55.
    Kok MB, de Vries A, Abdurrachim D, Prompers JJ, Grüll H, Nicolay K, Strijkers GJ (2011) Quantitative (1)H MRI, (19)F MRI, and (19)F MRS of cell-internalized perfluorocarbon paramagnetic nanoparticles. Contrast Media Mol Imaging 6(1):19–27. doi: 10.1002/cmmi.398 PubMedCrossRefGoogle Scholar
  56. 56.
    Jokerst JV, Gambhir SS (2011) Molecular imaging with theranostic nanoparticles. Acc Chem Res 44(10):1050–1060. doi: 10.1021/ar200106e PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Park JO, Stephen Z, Sun C, Veiseh O, Kievit FM, Fang C, Leung M, Mok H, Zhang M (2011) Glypican-3 targeting of liver cancer cells using multifunctional nanoparticles. Mol Imaging 10(1):69–77PubMedCentralPubMedGoogle Scholar
  58. 58.
    Dupeyron D, Kawakami M, Ferreira AM, Caceres-Velez PR, Rieumont J, Azevedo RB, Carvalho JCT (2013) Design of indomethacin-loaded nanoparticles: effect of polymer matrix and surfactant. Int J Nanomedicine 8:3467–3477. doi: 10.2147/ijn.s47621 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Reineke J, Cho DY, Dingle YL, Cheifetz P, Laulicht B, Lavin D, Furtado S, Mathiowitz E (2013) Can bioadhesive nanoparticles allow for more effective particle uptake from the small intestine? J Control Release 170(3):477–484. doi: 10.1016/j.jconrel.2013.05.043 PubMedCrossRefGoogle Scholar
  60. 60.
    Bravo-Osuna I, Vauthier C, Farabollini A, Palmieri GF, Ponchel G (2007) Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials 28(13):2233–2243. doi: 10.1016/j.biomaterials.2007.01.005 PubMedCrossRefGoogle Scholar
  61. 61.
    Mansour HM, Rhee YS, Wu XA (2009) Nanomedicine in pulmonary delivery. Int J Nanomed 4:299–319CrossRefGoogle Scholar
  62. 62.
    Sung JC, Pulliam BL, Edwards DA (2007) Nanoparticles for drug delivery to the lungs. Trends Biotechnol 25(12):563–570. doi: 10.1016/j.tibtech.2007.09.005 PubMedCrossRefGoogle Scholar
  63. 63.
    Shoyele SA, Cawthorne S (2006) Particle engineering techniques for inhaled biopharmaceuticals. Adv Drug Deliv Rev 58(9–10):1009–1029 (pii: S0169-409X(06)00145-1)PubMedCrossRefGoogle Scholar
  64. 64.
    Rytting E, Bur M, Cartier R, Bouyssou T, Wang X, Kruger M, Lehr CM, Kissel T (2010) In vitro and in vivo performance of biocompatible negatively-charged salbutamol-loaded nanoparticles. J Control Release 141(1):101–107 (pii: S0168-3659(09)00587-2)PubMedCrossRefGoogle Scholar
  65. 65.
    Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA (2002) Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci USA 99(19):12001–12005. doi: 10.1073/pnas.182233999 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Sung JC, Padilla DJ, Garcia-Contreras L, Verberkmoes JL, Durbin D, Peloquin CA, Elbert KJ, Hickey AJ, Edwards DA (2009) Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res 26(8):1847–1855. doi: 10.1007/s11095-009-9894-2 PubMedCrossRefGoogle Scholar
  67. 67.
    Lajavardi L, Bochot A, Camelo S, Goldenberg B, Naud MC, Behar-Cohen F, Fattal E, de Kozak Y (2007) Downregulation of endotoxin-induced uveitis by intravitreal injection of vasoactive intestinal peptide encapsulated in liposomes. Invest Ophthalmol Vis Sci 48(7):3230–3238. doi: 10.1167/iovs.06-1305 PubMedCrossRefGoogle Scholar
  68. 68.
    Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R (1978) Design of liposomes for enhanced local release of drugs by hyperthermia. Science 202(4374):1290–1293PubMedCrossRefGoogle Scholar
  69. 69.
    Hocine S, Li MH (2013) Thermoresponsive self-assembled polymer colloids in water. Soft Matter 9(25):5839–5861. doi: 10.1039/c3sm50428j CrossRefGoogle Scholar
  70. 70.
    Wood BJ, Poon RT, Locklin JK, Dreher MR, Ng KK, Eugeni M, Seidel G, Dromi S, Neennan Z, Kolf M, Black CDV, Prabhakar R, Libutti SK (2012) Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. J Vasc Interv Radiol 23(2):248–255. doi: 10.1016/j.jvir.2011.10.018 PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Rapoport N, Nam KH, Gupta R, Gao Z, Mohan P, Payne A, Todd N, Liu X, Kim T, Shea J, Scaife C, Parker DL, Jeong EK, Kennedy AM (2011) Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release 153(1):4–15.  10.1016/j.jconrel.2011.01.022 PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Castelletto V, McKendrick JE, Hamley IW, Olsson U, Cenker C (2010) PEGylated amyloid peptide nanocontainer delivery and release system. Langmuir 26(14):11624–11627. doi: 10.1021/la101806z PubMedCrossRefGoogle Scholar
  73. 73.
    de Smet M, Heijman E, Langereis S, Hijnen NM, Grüll H (2011) Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. J Control Release 150(1):102–110. doi: 10.1016/j.jconrel.2010.10.036 PubMedCrossRefGoogle Scholar
  74. 74.
    Bates S (2010) Progress towards personalized medicine. Drug Discov Today 15(3–4):115–120. doi: 10.1016/j.drudis.2009.11.001 PubMedCrossRefGoogle Scholar
  75. 75.
    Kateb B, Chiu K, Black KL, Yamamoto V, Khalsa B, Ljubimova JY, Ding H, Patil R, Portilla-Arias JA, Modo M, Moore DF, Farahani K, Okun MS, Prakash N, Neman J, Ahdoot D, Grundfest W, Nikzad S, Heiss JD (2011) Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: what should be the policy? Neuroimage 54(Suppl 1):S106–S124. doi:  10.1016/j.neuroimage.2010.01.105 PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Mura S, Couvreur P (2012) Nanotheranostics for personalized medicine. Adv Drug Deliv Rev 64(13):1394–1416. doi: 10.1016/j.addr.2012.06.006 PubMedCrossRefGoogle Scholar
  77. 77.
    Terreno E, Dastru W, Delli Castelli D, Gianolio E, Crich SG, Longo D, Aime S (2010) Advances in metal-based probes for MR molecular imaging applications. Curr Med Chem 17(31):3684–3700PubMedCrossRefGoogle Scholar
  78. 78.
    Giraudeau C, Flament J, Marty B, Boumezbeur F, Meriaux S, Robic C, Port M, Tsapis N, Fattal E, Giacomini E, Lethimonnier F, Le Bihan D, Valette J (2010) A new paradigm for high-sensitivity 19F magnetic resonance imaging of perfluorooctylbromide. Magn Reson Med 63(4):1119–1124. doi: 10.1002/Mrm.22269 PubMedCrossRefGoogle Scholar
  79. 79.
    Viglianti BL, Ponce AM, Michelich CR, Yu D, Abraham SA, Sanders L, Yarmolenko PS, Schroeder T, MacFall JR, Barboriak DP, Colvin OM, Bally MB, Dewhirst MW (2006) Chemodosimetry of in vivo tumor liposomal drug concentration using MRI. Magn Reson Med 56(5):1011–1018. doi: 10.1002/mrm.21032 PubMedCrossRefGoogle Scholar
  80. 80.
    Langereis S, Keupp J, van Velthoven JL, de Roos IH, Burdinski D, Pikkemaat JA, Grüll H (2009) A temperature-sensitive liposomal 1H CEST and 19F contrast agent for MR image-guided drug delivery. J Am Chem Soc 131(4):1380–1381. doi: 10.1021/ja8087532 PubMedCrossRefGoogle Scholar
  81. 81.
    Grüll H, Langereis S (2012) Hyperthermia-triggered drug delivery from temperature-sensitive liposomes using MRI-guided high intensity focused ultrasound. J Control Release 161(2):317–327. doi: 10.1016/j.jconrel.2012.04.041 PubMedCrossRefGoogle Scholar
  82. 82.
    Fabiilli ML, Lee JA, Kripfgans OD, Carson PL, Fowlkes JB (2010) Delivery of water-soluble drugs using acoustically triggered perfluorocarbon double emulsions. Pharm Res 27(12):2753–2765. doi: 10.1007/s11095-010-0277-5 PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Kim K, Kim JH, Park H, Kim YS, Park K, Nam H, Lee S, Park JH, Park RW, Kim IS, Choi K, Kim SY, Park K, Kwon IC (2010) Tumor-homing multifunctional nanoparticles for cancer theragnosis: simultaneous diagnosis, drug delivery, and therapeutic monitoring. J Control Release 146(2):219–227. doi: 10.1016/j.jconrel.2010.04.004 PubMedCrossRefGoogle Scholar

Copyright information

© Italian Association of Nuclear Medicine and Molecular Imaging 2014

Authors and Affiliations

  1. 1.Univ Paris-Sud, Institut Galien Paris-Sud, LabEx LERMIT, Faculté de PharmacieChâtenay-MalabryFrance
  2. 2.LabEx LERMIT, Institut Galien Paris-SudCNRS UMR 8612Châtenay-MalabryFrance

Personalised recommendations