Simple hybrid polymeric nanostructures encapsulating macro-cyclic Gd/Eu based complexes: luminescence properties and application as MRI contrast agent.

Lanthanide-based macrocycles are successfully incorporated into hybrid polyionic complexes, formed by adding a mixture of zirconium ions to a solution of a double-hydrophilic block copolymer. The resulting nanoobjects with an average radius of approximately 10-15 nm present good colloidal and chemical stability in physiological media even in the presence of competing ions such as phosphate or calcium ions. The final optical and magnetic properties of these objects benefit from both their colloidal nature and the specific properties of the complexes. Hence these new nanocarriers exhibit enhanced T1 MRI contrast, when administered intravenously to mice.

Iron-based hybrid polyionic complexes as chemical reservoirs for the pH-triggered synthesis of Prussian blue nanoparticles.

HYPOTHESIS: Hybrid polyion complexes (HPICs) obtained from the complexation in aqueous solution of a double hydrophilic block copolymer and metal ions can act as efficient precursors for the controlled synthesis of nanoparticles. In particular, the possibility to control the availability of metal ions by playing on the pH conditions is of special interest to obtain nanoparticles with controlled size and composition. EXPERIMENTS: HPICs based on Fe3+ ions were used to initiate the formation of Prussian blue (PB) nanoparticles in presence of potassium ferrocyanide in reaction media with varying pH values. FINDINGS: Complexed Fe3+ ions within HPICs can be easily released by adjusting the pH value either through the addition of a base/acid or by using a merocyanine photoacid. This allows to modulate the reactivity of Fe3+ ions with potassium ferrocyanide present in solution. As a result, PB nanoparticles with different structures (core, core-shell), composition and controlled size are obtained.

Diblock versus block-random copolymer architecture effect on physical properties of Gd3+-based hybrid polyionic complexes.

HYPOTHESIS: Random insertion of vinylphosphonic acid (VPA) units into a of PEG-PAA block copolymer improves the chemical stability and properties of hybrid nanoobjects obtained from the complexation of the copolymer with metal ions. EXPERIMENTS: Block polymers based on poly(acrylic acid) (PAA) and poly(ethylene glycol) (PEG) are modified by random insertion of 0 to 100 % of phosphonic acid functions in PAA block by a RAFT polymerization process. These polymers are then used to form hybrid polyionic complexes (HPICs) by complexation with gadolinium or europium ions. The properties of the obtained assemblies are evaluated by magnetic relaxivity, fluorescence and light scattering measurements. FINDINGS: The insertion of VPA units within the PAA block increases the chemical stability of the hybrid micelles by maintaining their integrity even at low pH. This insertion also minimizes the exchange of ions between HPICs and the surrounding medium thanks to a strengthening of interactions toward lanthanide ions. When such systems are used as MRI contrast agents or luminescent probe, 50/50 AA/VPA composition appears to be a good compromise to achieve optimal relaxivity or luminescent properties while ensuring a good chemical stability.

Gelation Mechanism Revealed in Organometallic Gels: Prevalence of van der Waals Interactions on Oligomerization by Coordination Chemistry.

Shaping of nanomaterials is a necessary step for their inclusion in electronic devices and batteries. For this purpose, the formulation of a moldable material including these nanomaterials is desirable. Organomineral gels are a very interesting option, since the components of the nanomaterial itself form a gel without the help of a binder. As a consequence, the properties of the nanomaterial are not diluted by the binder. In this article we studied organometallic gels based on a [ZnCy2 ] organometallic precursor and a primary alkyl amine which together forms spontaneously gels after few hours. We identified the main parameters controlling the gel properties monitored by rheology and NMR measurements The experiments demonstrate that the gelation time depends on the length of the alkyl chain of the amine and that the gelation mechanism derived firstly from the rigidification of the aliphatic chains of the amine, which takes precedence over the oligomerization of the inorganic backbone. This result highlights that the control of the rheological properties of organometallic gels remains mainly governed by the choice of the amine.

Assemblies of poly(N-vinyl-2-pyrrolidone)-based double hydrophilic block copolymers triggered by lanthanide ions: characterization and evaluation of their properties as MRI contrast agents.

Because of the formation of specific antibodies to poly(ethylene glycol) (PEG) leading to life-threatening side effects, there is an increasing need to develop alternatives to treatments and diagnostic methods based on PEGylated copolymers. Block copolymers comprising a poly(N-vinyl-2-pyrrolidone) (PVP) segment can be used for the design of such vectors without any PEG block. As an example, a poly(acrylic acid)-block-poly(N-vinyl-2-pyrrolidone) (PAA-b-PVP) copolymer with controlled composition and molar mass is synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Mixing this copolymer with lanthanide cations (Gd3+, Eu3+, Y3+) leads to the formation of hybrid polyion complexes with increased stability, preventing the lanthanide cytotoxicity and in vitro cell penetration. These new nanocarriers exhibit enhanced T1 MRI contrast, when intravenously administered into mice. No leaching of gadolinium ions is detected from such hybrid complexes.

Double-hydrophilic block copolymer-metal ion associations: Structures, properties and applications.

Hybrid polyionic complexes (HPICs), constructed from double-hydrophilic block copolymers and metal ions, have been largely developed with increasing interest in the past decade in the fields of catalysis, materials science and biological applications. The chemical natures of both blocks are very versatile, but one block should be able to interact with ions, and the second one should be neutral. Many metals have been used to form HPICs, which have, in their simplest architectural form, a core-shell structure of a few tens of nanometers in radius with an external shell made of the neutral block of the copolymer. In this review, we focus our discussion on the stability, shape, size and inner structure of these hybrid micelles. We then describe the most recent applications of HPICs, as reported in the literature, and point out the current challenges, missing structural information and future perspectives for this class of organized structures.

Assembly of Poly(vinylphosphonic acid)-Based Double Hydrophilic Block Copolymers by Gadolinium Ions for the Formation of Highly Stable MRI Contrast Agents.

Mixing double-hydrophilic block copolymers containing a poly(vinylphosphonic acid) block with gadolinium ions in water leads to the spontaneous formation of polymeric nanoparticles. With an average diameter near 20 nm, the nanoparticles are stable after dilution or change of pH and ionic strength. High magnetic relaxivities were measured in vitro, and in vivo magnetic resonance imaging on rats demonstrates the high potential of such polymeric assemblies.

Hybrid polymeric micelles stabilized by gallium ions: Structural investigation.

The addition of gallium ions to a solution of a double-hydrophilic block copolymer, i.e. poly(ethylene oxide)-block-poly(acrylic acid), leads to the spontaneous formation of highly monodisperse micelles with a Hybrid PolyIon Complexes (HPICs) core. By combining several techniques, a precise description of the HPIC architecture was achieved. In particular and for the first time, NMR and anomalous small angle X-ray scattering (ASAXS) enable tracking of the inorganic ions in solution and highlighting the co-localization of the gallium and the poly(acrylic acid) blocks in a rigid structure at the core of the micelle. Such a core has a radius of ca 4.3 nm while the complete nano-object with its poly(ethylene oxide) shell has a total radius of ca 11 nm. The aggregation number was also estimated using the ASAXS results. This comprehensive structural characterization of the Ga HPICs corroborates the assumptions made for HPICs based on other inorganic ions and demonstrates the universality of the HPIC structure leading, for example, to new families of contrast agents in medical imaging.

Mechanistic insights into the anisotropic growth of ZnO nanoparticles deciphered through 2D size plots and multivariate analysis.

The control and understanding of the nucleation and growth of nano-objects are key points for improving and/or considering the new applications of a given material at the nanoscale. Mastering the morphology is essential as the final properties are drastically affected by the size, shape, and surface structure. Yet, a number of challenges remain, including evidencing and understanding the relationship between the experimental parameters of the synthesis and the shape of the nanoparticles. Here we analyzed jointly and in detail the formation of anisotropic ZnO nanoparticles under different experimental conditions by using two different analytical tools enabling the analysis of TEM images: 2D size plots and multivariate statistical analysis. Well-defined crystalline ZnO nanorods were obtained through the hydrolysis of a dicyclohexyl zinc precursor in the presence of a primary fatty amine. Such statistical tools allow one to fully understand the effect of experimental parameters such as the hydrolysis rate, the mixing time before hydrolysis, the length of the ligand aliphatic chain, and the amount of water. All these analyses suggest a growth process by oriented attachment. Taking advantage of this mechanism, the size and aspect ratio of the ZnO nanorods can be easily tuned. These findings shed light on the relative importance of experimental parameters that govern the growth of nano-objects. This general methodological approach can be easily extended to any type of nanoparticle.

Anisotropic growth of ZnO nanoparticles driven by the structure of amine surfactants: the role of surface dynamics in nanocrystal growth.

Herein, we elucidate the key role of amine surfactants in the controlled anisotropic growth of ZnO nanoparticles that is achieved under mild conditions by organometallic hydrolysis. The structuring influence of alkyl substituents on the nitrogen atom of amines is jointly analyzed theoretically by DFT modeling, and experimentally by multinuclear NMR (1H, 13C and 17O) spectroscopy. We demonstrate that in initial steps leading to the growth of colloidal ZnO particles, the nature of molecular species that are involved in the solution strongly depends on the structure of the amine surfactant. By using tertiary, secondary or primary amines, no or weak adducts between the amine and zinc, or stable adducts, or adduct oligomers were identified, respectively. Afterwards, following the course of the reaction, the dynamic behavior of the amines on the grown ZnO nanocrystal surfaces is also strongly correlated with their structure. We identified that in the presence of tertiary, secondary or primary amines, no significant [Zn⋯N] adsorption, or surface adsorption with notable surface mobility, or a very strong adsorption is achieved, respectively. The last case, primary amines, significantly involves the structuring of a hydrogen bonding network. Therefore, such surface dynamic behavior has a predominant role in driving the nanocrystal growth, and orienting the ZnO material final morphology. By forming hydrogen bonds at the nanoparticle surface during the growth process, primary amines specifically lead to the formation of nanorods. Conversely, isotropic nanoparticles and aggregates are obtained when secondary and tertiary amines are used, respectively. These findings shed light on the role of weak surface interactions, herein H-bonding, that rule the growth of nano-objects and are as such crucial to identify, study, and control for achieving progress in nanoscience.

Copper-Based Hybrid Polyion Complexes for Fenton-Like Reactions.

An innovative strategy allowing the development of a new generation of easy-to-prepare and easy-to-use nano-sized catalysts with high tenability is presented. This strategy is based on the formation of hybrid polyion complexes (HPICs) from the complexation of copper with a block copolymer consisting of an ionizable complexing block and a neutral stabilizer block. These complexes have a well-defined structure and size with a hydrodynamic diameter around 29 nm. They are stable in aqueous solution over a pH range from 4 to 8 and are not sensitive to NaCl salt addition or dilution effects. As a proof-of-concept the degradation of naphthol blue black in water through the use of the Fenton or photo-Fenton reaction is studied. Their performances are comparable to a classical homogeneous reaction, whereas HPICs are easily recyclable by simple dialysis.

Quench ionic flash nano precipitation as a simple and tunable approach to decouple growth and functionalization for the one-step synthesis of functional LnPO4-based nanoparticles in water.

A novel, one-step method for the synthesis of functional, organic-inorganic hybrid nanoparticles is reported. The quench ionic Flash NanoPrecipitation (qiFNP) method enables the straightforward synthesis of nanoparticles by decoupling the formation of the inorganic core and surface functionalization. As a proof-of-concept, the qiFNP method was successfully applied for the tunable and highly controlled synthesis of various LnPO4-based nanomaterials for bioimaging applications.

Frit inlet field-flow fractionation techniques for the characterization of polyion complex self-assemblies.

Polymer self-assemblies joining oppositely charged chains, known as polyion complexes (PICs), have been formed using poly(ethyleneoxide - b - acrylic acid)/poly(l-lysine), poly(ethyleneoxide-b-acrylic acid)/dendrigraft poly(l-lysine) and poly[(3-acrylamidopropyl) trimethylammonium chloride - b - N - isopropyl acrylamide]/poly(acrylic acid). The self-assemblies have been first characterized in batch by Dynamic Light Scattering. In a second step, their analysis by Flow Field-Flow Fractionation techniques (FlFFF) was examined. They were shown to be very sensitive to shearing, especially during the focus step of the fractionation, and this led to an incompatibility with asymmetrical FlFFF. On the other hand, Frit Inlet FlFFF proved to be very efficient to observe them, either in its symmetrical (FI-FlFFF) or asymmetrical version (FI-AsFlFFF). Conditions of elution were found to optimize the sample recovery in pure water. Spherical self-assemblies were detected, with a size range between 70-400nm depending on the polymers. Compared to batch DLS, FI-AsFlFFF clearly showed the presence of several populations in some cases. The influence of salt on poly(ethyleneoxide-b-acrylic acid) (PEO-PAA) 6000-3000/dendrigraft poly(l-lysine) (DGL 3) was also assessed in parallel in batch DLS and FI-AsFlFFF. Batch DLS revealed a first process of swelling of the self-assembly for low concentrations up to 0.8M followed by the dissociation. FI-AsFlFFF furthermore indicated a possible ejection of DGL3 from the PIC assembly for concentrations as low as 0.2M, which could not be observed in batch DLS.

Drug Release by Direct Jump from Poly(ethylene-glycol-b-ε-caprolactone) Nano-Vector to Cell Membrane.

Drug delivery by nanovectors involves numerous processes, one of the most important being its release from the carrier. This point still remains unclear. The current work focuses on this point using poly(ethyleneglycol-b-ε-caprolactone) micelles containing either pheophorbide-a (Pheo-a) as a fluorescent probe and a phototoxic agent or fluorescent copolymers. This study showed that the cellular uptake and the phototoxicity of loaded Pheo-a are ten times higher than those of the free drug and revealed a very low cellular penetration of the fluorescence-labeled micelles. Neither loaded nor free Pheo-a displayed the same cellular localization as the labeled micelles. These results imply that the drug entered the cells without its carrier and probably without a disruption, as suggested by their stability in cell culture medium. These data allowed us to propose that Pheo-a directly migrates from the micelle to the cell without disruption of the vector. This mechanism will be discussed.

One-Step Synthesis of Hybrid Liquid-Crystal ZnO Nanoparticles: Existence of a Critical Temperature Associated with the Anisotropy of the Nanoparticles.

Zinc oxide nanoparticles were obtained from the hydrolysis of an organometallic precursor in pure hexadecylamine. Interestingly, we demonstrate that the final (anisotropic or isotropic) shape of the nanoparticles is strongly correlated to the existence of a critical temperature. This suggests that the organization of the fatty amines is a paramount parameter in this synthesis. Moreover, the final hybrid ZnO materials systematically exhibit a liquid-crystal smectic phase, whereas no liquid-crystal phase was observed in the pristine reaction media. This simple process is, therefore, a direct and straightforward method to synthesize liquid-crystal hybrid materials.

Importance of the Correlation between Width and Length in the Shape Analysis of Nanorods: Use of a 2D Size Plot To Probe Such a Correlation.

Analysis of nanoparticle size through a simple 2D plot is proposed in order to extract the correlation between length and width in a collection or a mixture of anisotropic particles. Compared to the usual statistics on the length associated with a second and independent statistical analysis of the width, this simple plot easily points out the various types of nanoparticles and their (an)isotropy. For each class of nano-objects, the relationship between width and length (i.e., the strong or weak correlations between these two parameters) may suggest information concerning the nucleation/growth processes. It allows one to follow the effect on the shape and size distribution of physical or chemical processes such as simple ripening. Various electron microscopy pictures from the literature or from the authors' own syntheses are used as examples to demonstrate the efficiency and simplicity of the proposed 2D plot combined with a multivariate analysis.

Self-assembled polymeric vectors mixtures: characterization of the polymorphism and existence of synergistic effects in photodynamic therapy.

The objective of this work was to assess the relation between the purity of polymeric self-assemblies vectors solution and their photodynamic therapeutic efficiency. For this, several amphiphilic block copolymers of poly(ethyleneoxide-b-ε-caprolactone) have been used to form self-assemblies with different morphologies (micelles, worm-like micelles or vesicles). In a first step, controlled mixtures of preformed micelles and vesicles have been characterized both by dynamic light scattering and asymmetrical flow field flow fractionation (AsFlFFF). For this, a custom-made program, STORMS, was developed to analyze DLS data in a thorough manner by providing a large set of fitting parameters. This showed that DLS only sensed the larger vesicles when the micelles/vesicles ratio was 80/20 w/w. On the other hand, AsFlFFF allowed clear detection of the presence of micelles when this same ratio was as low as 10/90. Subsequently, the photodynamic therapy efficiency of various controlled mixtures was assessed using multicellular spheroids when a photosensitizer, pheophorbide a, was encapsulated in the polymer self-assemblies. Some mixtures were shown to be as efficient as monomorphous systems. In some cases, mixtures were found to exhibit a higher PDT efficiency compared to the individual nano-objects, revealing a synergistic effect for the efficient delivery of the photosensitizer. Polymorphous vectors can therefore be superior in therapeutic applications.

Assembly of Double-Hydrophilic Block Copolymers Triggered by Gadolinium Ions: New Colloidal MRI Contrast Agents.

Mixing double-hydrophilic block copolymers containing a poly(acrylic acid) block with gadolinium ions in water leads to the spontaneous formation of polymeric nanoparticles. With an average diameter near 20 nm, the nanoparticles are exceptionally stable, even after dilution and over a large range of pH and ionic strength. High magnetic relaxivities were measured in vitro for these biocompatible colloids, and in vivo magnetic resonance imaging on rats demonstrates the potential utility of such polymeric assemblies.

Hyperbranched polymer mediated size-controlled synthesis of gadolinium phosphate nanoparticles: colloidal properties and particle size-dependence on MRI relaxivity.

Hyperbranched polymers based on the poly(amidoamine), HyPAM, were used to synthesize gadolinium phosphate nanowires under mild conditions. Control of the average particle size was obtained by adjusting polymer concentration. Proton relaxivity measurements reveal an optimum particle size, reaching relaxivity values as high as 55 ± 9 mM(-1) s(-1) for r1 and 67 ± 11 mM(-1) s(-1) for r2. The colloidal stability of these hybrid systems were optimized through the use of functionalized core-shell polymers containing PEG segments and C18-PEG segments, structures which also offer the possibility of imparting additional function into the polymer-particle hybrids.

Liquid crystalline thermotropic and lyotropic nanohybrids.

This review is meant to give the reader an insight into hybrids incorporating different types of nanoparticles, e.g. metallic or metal oxides, within different types of lyotropic and thermotropic liquid crystals, from relatively small calamitic molecules to the larger discotics and polymers. In particular, this review highlights the importance of nanoparticle-liquid crystal interactions in accessing hybrid materials that exhibit synergetic properties.