Audrey Parat

Covalent Layer-by-Layer Assemblies of Polyelectrolytes and Homobifunctional Spacers

The step-by-step buildup of organic films through physical or covalent bonds is usually performed by the alternating adsorption of two types of polymeric chains. Overcompensation of the interacting groups after each deposition step (e.g., charge overcompensation in the case of polyelectrolyte multilayers) allows the buildup process to proceed. This overcompensation is intimately linked to the polymeric nature of the interacting species. We report here another type of film architecture also based on step-by-step construction but involving the covalent bonding, through the Sharpless click reaction, between polyelectrolytes (i.e., polyanions) and neutral bifunctional molecules. The films are built by the Cu(I)-catalyzed click reaction of poly(acrylic acid) (PAA) functionalized with ethylene glycol (EG) arms, each ending with either an alkyne or an azide group, and bifunctionalized EG spacers ended with either alkyne or azide functions. We prove that these systems lead to the regular buildup of films that cover the whole substrate surface and whose roughness varies as the thickness of the film core. The effects of various parameters on film buildup are investigated. The grafting density of reactive moieties along the PAA chains has no influence on the thickness increment per bilayer. EG spacers bifunctionalized with alkyne groups reacting with PAA chains functionalized with azide arms give films that grow more rapidly than those obtained with azide-functionalized EG spacers and alkyne-functionalized PAA chains. The influence of the length of the EG arm (grafted on PAA) and of the EG spacer on the film buildup is also investigated: longer arms or longer spacers lead to larger thickness increments per bilayer, except for very large spacers of 50 EG units for which the thickness is the smallest probably because of size exclusion effects during the deposition.

One-pot morphogen driven self-constructing films based on non-covalent host–guest interactions

The construction of films with complex architectures through one-pot reactions taking place exclusively on a surface remains a challenge. Recently, to address this problem, we introduced a concept based on morphogen-driven film buildup. We used Cu(I) as morphogen and the Huisgens click-reaction between azide and alkyne groups on polymers as film building blocks. Here, we extend this concept to films whose integrity is based exclusively on non-covalent host–guest interactions that are reversible allowing much broader tunability of the film properties. We trigger electrochemically the self-construction of films based on clickable host (cyclodextrin) and guests (ferrocene or adamantane) both functionalized by alkyne functions and poly(acrylic acid) bearing azide groups. Under voltammetry cycles, where Cu(I) is formed in situ from Cu(II), the film builds up by the non-reversible covalent grafting of the host and guest molecules to poly(acrylic acid) chains through triazole formation and by the subsequent formation of reversible host–guest interactions which entirely support the film cohesion. This process leads to the continuous self-construction of a nanometre size film whose thickness increases with the application time of the electrochemical stimulus. The growth rate of the film can be tuned by changing in the buildup solution either the relative ratio in concentration of host and guest or through the competition between clickable and non-clickable guest molecules. The effect of different stimuli leading to the dissolution of the film is also reported.

Dendrimer–nanoparticle conjugates in nanomedicine

Nanomedicine can take advantage of the recent developments in nanobiotechnology research areas for the creation of platforms with superior drug carrier capabilities, selective responsiveness to the environment, unique contrast enhancement profiles and improved accumulation at the disease site. Colloidal inorganic nanoparticles (NPs) have been attracting considerable interest in biomedicine, from drug and gene delivery to imaging, sensing and diagnostics. It is essential to modify the NPs surface to have enhanced biocompatibility and reach multifunctional systems for the in vitro and in vivo applications, especially in delivering drugs locally and recognizing overexpressed biomolecules. This paper describes the rational design for dendrimer-nanoparticle conjugates elaboration and reviews their state-of-the-art uses as efficient nanomedicine tools.

Validation of a dendron concept to tune colloidal stability, MRI relaxivity and bioelimination of functional nanoparticles

The functionalization of spherical superparamagnetic iron oxide nanoparticles (SPION) of 10 nm with a linear monophosphonate (L1) and also PEGylated mono-phosphonated dendrons of growing generation (D2-G1, -G2 and -G3) yielded dendritic nano-objects of 15 to 30 nm in size, stable in physiological media and showing both renal and hepatobiliary elimination. The grafting of the different molecules has been confirmed by IR spectroscopy and elemental analysis. The colloidal stability of functionalized NS10 has been evaluated in water and in different physiological media. All functionalized NS10 were stable over a long period of time and displayed a mean hydrodynamic diameter smaller than 50 nm whatever the molecule architecture or dendron generation. Only the NS10@L1 showed less stability in biological media at high ionic concentration. NMRD profiles and relaxivity measurements highlighted the influence of the molecule architecture on the water diffusion close to the magnetic core thus influencing the relaxation properties at low magnetic field. Coupling of a fluorescent dye on the functionalized NS10 allowed investigating their biodistribution and highlighting urinary and hepato-biliary eliminations.

Efficient synthesis of small-sized phosphonated dendrons: potential organic coatings of iron oxide nanoparticles

We report herein the synthesis of biocompatible small-sized phosphonated monomers and dendrons used as functional coatings of metal oxide nanoparticles, more specifically superparamagnetic iron oxides (SPIOs) for magnetic resonance imaging (MRI) and therapy through hyperthermia. The molecules were engineered to modulate their size, their hydrophilic and/or biocompatible character (poly(amido)amine versus oligoethyleneglycol), the number of anchoring phosphonate groups (monophosphonate versus phosphonic tweezers) and the number of peripheral functional groups for further grafting of dyes or specific vectors. Such a library of hydrophilic phosphonic acids opens new possibilities for the investigation of dendronized nanohybrids as theranostics.

Influence of the interaction strength between supramolecular complexes on the topography of neutral polymer multilayer films.

Step-by-step polymer film buildup processes lead to polymer coatings, e.g., polyelectrolyte multilayers, of various structures ranging from continuous smooth films to droplet like discontinuous coatings. Yet, the origin of these different behaviors depending upon the system is not yet known. This study is a first attempt to rationalize the evolution of the coating structure as a function of the strength of the interactions between the polymers constituting the film. We investigated the influence of the strength of noncovalent host-guest interactions between cyclodextrin (CD) and pyrene (Py), ferrocene (Fc) or adamantane (Ad) on the structure of neutral poly(N-hydroxypropylmethacrylamide) (PHPMA) multilayers films formed in a step-by-step manner. In solution, the strength of the inclusion complex (measured by log K where K is the complex association constant) is increasing in the order Py/β-CD < Fc/β-CD < Ad/β-CD and can be further varied in the presence of different sodium salts at different ionic strengths. Depending upon this strength, the buildup process is limited to the formation of isolated aggregates for PHPMA-CD/PHPMA-Py, leading to smooth continuous films for PHPMA-CD/PHPMA-Fc and to droplet-like films, not entirely covering the substrate, for PHPMA-CD/PHPMA-Ad. To study the influence of the strength of the host-guest interactions on the film topography, PHPMA-CD/PHPMA-Fc films were built in the presence of different sodium salts at different ionic strengths. For low host-guest interactions, only isolated aggregates are formed on the substrate. As the strength of the host-guest interactions increases (increase of log K), the formed films go through a droplet-like structure, before becoming continuous but rough for stronger interactions. When the interaction strength is further increased, the roughness of the films decreases, leading to a smooth continuous film before becoming rough again at still higher interaction strength. Smooth continuous multilayers seem thus to be obtained for an optimal range of the interaction strength.

Functionalization strategies and dendronization of iron oxide nanoparticles

Abstract The explosive growth of nanotechnology has brought challenging innovations in the synthesis of multifunctional nano-objects able to revolutionize the field of diagnosis and therapy in medicine. Furthermore, one important input of today’s nanotechnology in biology is that their design will also allow real progress to achieve temporal and spatial site local therapy and imaging. Such a breakthrough is made possible by the development of multifunctional biocompatible nanosystems resulting from cutting-edge researches based on pluridisciplinary approaches. Among the challenges are the design of the organic coating and its grafting at the surface of NPs while preserving the properties of both NPs and molecules. The molecules should ensure the colloidal stability of NPs in physiological media, their biocompatibility and biodistribution, and may bear functions to couple bioactive groups. This paper aims at providing challenges in functionalization of iron oxide nanoparticles for biomedical applications.

Radiolabeled dendritic probes as tools for high in vivo tumor targeting: application to melanoma

In bioimaging, targeting allows refining the diagnosis by improving the sensitivity and especially the specificity for an earlier diagnosis. Two 111In-radiolabeled dendritic nanoprobes (DPs) (111In-2, 111In-3) and their model counterparts (111In-1, 111In-4) are designed and assessed for in vitro and in vivo tumor targeting efficiency in a murine melanoma models. Tumor uptake is correlated to dendrimer multivalency and reaches values as high as 12.7 ± 1.6% ID g-1 at 4 h post intravenous injection for 111In-3vs. 1.5 ± 0.5% ID g-1 for the unfunctionalized DP, and over 11% ID g-1 for any tumor weight whatsoever.

Preparation of core/shell NaYF4:Yb,Tm@dendrons nanoparticles with enhanced upconversion luminescence for in vivo imaging

Upconverting nanoparticles (UCNPs) were successfully dendronized for fluorescence medical imaging applications. The structural and morphological characterizations of resulting core/shell NaYF4:Yb,Tm@dendrons nanoparticles were performed by means of X-ray diffraction, infrared spectroscopy and transmission electron microscopy. In vitro cytotoxicity assays have evidenced their low toxicity. In vivo fluorescence imaging study was performed in mice upon IR excitation, showing promising imaging capacities at low concentrations (0.5mg/mL) and low power (50mW/cm2).

Chapter 4:Iron-oxide Nanoparticle-based Contrast Agents

This chapter discusses the synthesis, functionalization, characterization, and imaging applications of iron-oxide-nanoparticle-based contrast agents. By reducing the size from bulk to the nanometer scale (<20 nm), ferrimagnetic iron oxide acquires a magnetic property called superparamagnetism, which is key to the potential of these particles as MRI contrast agents. This chapter describes the theory governing the relaxivity of nanoparticle-based contrast agents. The different syntheses, coatings, and functionalization approaches are then discussed, including how these syntheses affect the properties of the nanomaterial. Different techniques for the characterization of the cores and coatings of nanoparticles, including their size and composition, are then discussed. Particular attention is given to characterization of the magnetic properties of iron oxide nanoparticles. Finally, the acquisition of MRI phantoms is presented.