Publikationen

15.04.2020

Polyanionic Hydrogels as Reservoirs for Polycationic Antibiotic Substitutes Providing Prolonged Antibacterial Activity

In ACS Appl. Mater. Interfaces

Implantation of biomedical devices is often followed by bacterial infections that may seriously affect implant functionalities and lead to their failure. In the context of bacterial resistance to antibiotics, which is a growing problem worldwide, new strategies that are able to overcome these problems are needed. In this work, we introduce a new formulation of hyaluronic acid (HA)-based antimicrobial material: HA hydrogels loaded with polyarginine (PAR), a polycationic antibiotic substitute. The loading is possible through electrostatic interactions between negatively charged HA and positively charged PAR. Such hydrogels absorb high quantities of PAR, which are then gradually released from the hydrogel. This original system provides a long-lasting antibacterial effect on an in vitro model of repetitive infection, thus demonstrating a strong potential to fight multiple rounds of infections that are resistant to antibiotic treatment. In addition, HA-PAR hydrogels could be deposited onto/into medical devices such as wound dressings and mesh prostheses used in clinical applications. Finally, we performed first in vivo tests of hydrogel-coated mesh materials to verify their biocompatibility in a rat model, which show no difference between control HA hydrogel and PAR-loaded hydrogel in terms of inflammation.

Varvara Gribova, Fouzia Boulmedais, Agnès Dupret-Bories, Cynthia Calligaro, Bernard Senger, Nihal Engin Vrana, Philippe Lavalle

Publication online here

 

15.02.2020

Unexpected aqueous UCST behavior of a cationic comb polymer with pentaarginine side chains

In European Polymer Journal

Thermoresponsive polymers, undergoing a reversible chemical or physical change using temperature as stimulus, attract increasing interest in particular as adaptable biomaterials. Except for zwitterionic polymers, fully charged polymers require the presence of specific ions to exhibit an upper critical solution temperature (UCST) in water. Herein, we report the discovery of an UCST in pure water for fully cationic comb polymers based on oligoarginine pendent grafts. These polymers were prepared using an original strategy based on solid-phase peptide synthesis of pentaarginine methacrylate-based macromonomer and its polymerization through reversible addition-fragmentation chain transfer. Despite their cationic nature, guanidinium groups from the arginine have the ability to self-associate at low temperature through hydrophobic interactions into stacked pair configuration defying the expected Coulomb interactions. These results pave the way to biomedical applications such as antimicrobial materials and drug delivery systems through the tuning of the polymer structure.

 

Nicolas Zydziak, Muhammad Haseeb Iqbal, Alain Chaumont, Antoine Combes,
Emeric Wasielewski, Mélanie Legros, Loïc Jierry, Philippe Lavalle, Fouzia Boulmedais,
Delphine Chan-Seng

Publication online here

 

30.01.2020

Mastering bioactive coatings of metal oxide nanoparticles and surfaces through phosphonate dendrons

In New Journal of Chemistry

We reported herein an efficient method for constructing dendritic bisphosphonic acid tweezers of generation 1 and 2, which have been proven as versatile surface coatings for metal oxides implants or nanoparticles. These dendritic structures were successfully utilized for different purposes: (i) biocompatible coverings for iron oxide nanoparticles through in vitro assays, (ii) antifouling surface coatings for silica through quartz crystal microbalance studies, and (iii) stabilizing ligands for magnetic nanoparticle–microbubble conjugates via preliminary Langmuir monolayer studies.

Dinh-Vu Nguyen, Ludivine Hugoni, Miriam Filippi, Francis Perton, Da Shi, Emilie Voirin, Laura Power, Geoffrey Cotin, Marie-Pierre Krafft, Arnaud Scherberich, Philippe Lavalle, Sylvie Begin-Colin, and Delphine Felder-Flesch

Publication online here

 

06.01.2020

Influence of Semifluorinated Alkane Surface Domains on Phase Behavior and Linear and Nonlinear Viscoelasticity of Phospholipid Monolayers

In Langmuir

Semifluorinated alkanes self-assemble into 30–40 nm-large surface domains (hemimicelles) at the air/water interface. They have been drawing increasing attention to stabilize microbubbles coated with lipids, which are used for enhancing the contrast in sonographic imaging. Although previous studies suggested that semifluorinated alkanes increase the stability of phospholipid membranes, little is known about how semifluorinated alkanes influence phase behaviors and mechanical properties of lipid-coated microbubbles. As a well-defined model of microbubble surfaces, we prepared monolayers consisting of a mixture of phospholipids and semifluorinated alkanes at the air/water interface and investigated the influence of hemimicelles of semifluorinated alkanes on the phase behavior and interfacial viscoelastic properties of phospholipid monolayers. Hemimicelles are phase-separated from phospholipids and accumulate at the phase boundary, which strongly modulates the correlation between solid phospholipid domains. Intringuingly, we found that the mixed monolayer of semifluorinated alkanes and phospholipids possesses linear and nonlinear viscoelastic properties comparable to those of phospholipid monolayers. Since the mixing of semifluorinated alkanes and phospholipids enables one to overcome the intrinsically low stability of pure semifluorinated alkanes against the change in the surface area of microbubbles through the partial dissolution of gas into the aqueous phase, this is a promising strategy for the stable coating of microbubbles in ultrasound diagnosis.

Salomé Mielke, Xianhe Liu, Marie Pierre Krafft, and Motomu Tanaka

Publication online here

 

23.12.2019

Surface texturation of breast implant alters extracellular matrix and inflammatory gene expression even in asymptomatic capsule

In Plastic and Reconstructive Surgery

Texturing processes have been designed to improve biocompatibility and mechanical anchoring of breast implants. However, recent findings linked high texturation degree to severe pathologies. Until now, asymptomatic capsules are considered similar irrespective of the type of breast implant surface they face. Objectives : In this paper, we envisaged for the first time that implant surface topography could even affects healthy capsule organization. Materials and methods: We collected topographical measurements from 17 different breast implant devices using interferometry and X-ray Microtomography. Morphological structures were statistically analyzed to raise a robust breast implant surface classification. In parallel, we collected 31 Baker I capsules, sorted them accordingly to the new classification, established their molecular profile and examined related tissue organization on histological sections. A panel of extracellular matrix (Timp1, Timp2, Timp4, Mmp2, Mmp9, Mmp12) and inflammatory related (Saa1, Tnsf11, Il8, Tgfβ1) genes were analysed by performing quantitative PCR (qPCR) experiments on healthy capsules strictly. Results: The new classification resulted in 3 topographical categories of textured implants, defined as „peak and valleys“, „open pores“ and „semi-closed cavities“ based on their cross-section aspect. By comparing capsular tissues from different implants, we found that genes associated with extracellular matrix (Timp and Mmp members) and to the inflammatory response (Saa1, Tnsf11, Il8) exhibit very specific expression patterns, despite originating from healthy capsules. Besides, organization of the capsular tissues was slightly impacted. Conclusions: By combining a novel surface implant classification with gene profiling analysis, we show that surface topography is a bioactive cue that can trigger deep changes in gene expression of the surrounding tissue, even in Baker I capsule. Altogether, our results validate our new classification and suggest that breast implant topography might partly promote the development of breast-implant associated complications.

Isabelle Brigaud, Charles Garabedian, Nathalie Bricout, Laurent Pieuchot, Arnaud Ponche, Raphael Deltombe, Rémy Dellile, Michael Atlan, Maxence Bigerelle, Karine Anselme

Publication online here

 

14.11.2019

Interfacial Behavior of Oligo(Ethylene Glycol) Dendrons Spread Alone and in Combination with a Phospholipid as Langmuir Monolayers at the Air/Water Interface

In Molecules

Dendrons consisting of two phosphonate functions and three oligo(ethylene glycol) (OEG) chains grafted on a central phenoxyethylcarbamoylphenoxy group were synthesized and investigated as Langmuir monolayers at the surface of water. The OEG chain in the para position was grafted with a t-Bu end-group, a hydrocarbon chain, or a partially fluorinated chain. These dendrons are models of structurally related OEG dendrons that were found to significantly improve the stability of aqueous dispersions of iron oxide nanoparticles when grafted on their surface. Compression isotherms showed that all OEG dendrons formed liquid-expanded Langmuir monolayers at large molecular areas. Further compression led to a transition ascribed to the solubilization of the OEG chains in the aqueous phase. Brewster angle microscopy (BAM) provided evidence that the dendrons fitted with hydrocarbon chains formed liquid-expanded monolayers throughout compression, whilst those fitted with fluorinated end-groups formed crystalline-like domains, even at large molecular areas. Dimyristoylphosphatidylcholine and dendron molecules were partially miscible in monolayers. The deviations to ideality were larger for the dendrons fitted with a fluorocarbon end-group chain than for those fitted with a hydrocarbon chain. Brewster angle microscopy and atomic force microscopy supported the view that the dendrons were ejected from the phospholipid monolayer during the OEG conformational transition and formed crystalline domains on the surface of the monolayer.

Da Shi, Dinh-Vu Nguyen, Mounir Maaloum, Jean-Louis Gallani, Delphine Felder-Flesch and Marie-Pierre Krafft

Publication online here

 

13.11.2019

Use of nanoparticles in skeletal tissue regeneration and engineering

In Histology and Histopathology

Bone and osteochondral defects represent one of the major causes of disabilities in the world. Derived from traumas and degenerative pathologies, these lesions cause severe pain, joint deformity, and loss of joint motion. The standard treatments in clinical practice present several limitations. By producing functional substitutes for damaged tissues, tissue engineering has emerged as an alternative in the treatment of defects in the skeletal system. Despite promising preliminary clinical outcomes, several limitations remain. Nanotechnologies could offer new solutions to overcome those limitations, generating materials more closely mimicking the structures present in naturally occurring systems. Nanostructures comparable in size to those appearing in natural bone and cartilage have thus become relevant in skeletal tissue engineering. In particular, nanoparticles allow for a unique combination of approaches (e.g. cell labelling, scaffold modification or drug and gene delivery) inside single integrated systems for optimized tissue regeneration. In the present review, the main types of nanoparticles and the current strategies for their application to skeletal tissue engineering are described. The collection of studies herein considered confirms that advanced nanomaterials will be determinant in the design of regenerative therapeutic protocols for skeletal lesions in the future.

Miriam Filippi, Gordian Born, Delphine Felder-Flesch and Arnaud Scherberich

Publication available here

 

30.10.2019

Metronidazole-functionalized iron oxide nanoparticles for molecular targeting of hypoxic tissue

In Nanoscale

Being crucial in several pathologic conditions, tumors, and tissue engineering, MRI tracing of the hypoxia within cells and tissues would be improved by the use of nanosystems allowing for direct targeting of low oxygenation and further treatment-oriented development. In the present study, we functionalized dendron-coated iron oxide nanoparticles (dendronized IONPs) with a bioreductive compound, a metronidazole-based ligand, to specifically recognize the hypoxic tissues. Spherical IONPs with an average size of 10 nm were obtained and then decorated with the new metronidazole-conjugated dendron. The resulting nanoparticles (metro-NPs) displayed negligible effects on cell viability, proliferation, and metabolism in both monolayer and 3D cell culture models, and a good colloidal stability into bio-mimicking media, as shown by DLS. Overtime quantitative monitoring of the IONP cell content revealed an enhanced intracellular retention of metro-NPs under anoxic conditions, confirmed by in vitro MRI of cell pellets where a stronger negative contrast generation was observed into hypoxic primary stem cells and tumor cells after labeling with metro-NPs. Overall, these results suggest desirable properties in terms of interactions with the biological environment and the active targeting of the hypoxic tissue, and indicate that metro-NPs have considerable potential for the development of new nano-platforms especially in the field of anoxia-related diseases and tissue engineered models.

Miriam Filippi, Dinh-Vu Nguyen, Francesca Garello, Francis Perton, Sylvie Bégin-Colin,
Delphine Felder-Flesch, Laura Power, and Arnaud Scherberich

Publication available here

 

05.09.2019

Magnetic nanocomposite hydrogels and static magnetic field stimulate the osteoblastic and vasculogenic profile of  adipose-derived cells

In Biomaterials

Exposure of cells to externally applied magnetic fields or to scaffolding materials with intrinsic magnetic properties (magnetic actuation) can regulate several biological responses. Here, we generated novel magnetized nanocomposite hydrogels by incorporation of magnetic nanoparticles (MNPs) into polyethylene glycol (PEG)-based hydrogels containing cells from the stromal vascular fraction (SVF) of human adipose tissue. We then investigated the effects of an external Static Magnetic Field (SMF) on the stimulation of osteoblastic and vasculogenic properties of the constructs, with MNPs or SMF alone used as controls. MNPs migrated freely through and out of the material following the magnetic gradient. Magnetically actuated cells displayed increased metabolic activity. After 1 week, the enzymatic activity of Alkaline Phosphatase (ALP), the expression of osteogenic markers (Runx2, Collagen I, Osterix), and the mineralized matrix deposition were all augmented as compared to controls. With magnetic actuation, strong activation of endothelial, pericytic and perivascular genes paralleled increased levels of VEGF and an enrichment in the CD31+ cells population. The stimulation of signaling pathways involved in the mechanotransduction, like MAPK8 or Erk, at gene and protein levels suggested an effect mediated through the mechanical stimulation. Upon subcutaneous implantation in mice, magnetically actuated constructs exhibited denser, more mineralized and faster vascularized tissues, as revealed by histological and micro-computed tomographic analyses. The present study suggests that magnetic actuation can stimulate both the osteoblastic and vasculogenic potentials of engineered bone tissue grafts, likely at least partially by mechanically stimulating the function of progenitor cells.

Miriam Filippi, Boris Dasen, Julien Guerrero, Francesca Garello, Giuseppe Isu,
Gordian Born, Martin Ehrbar, Ivan Martin, Arnaud Scherberich

Publication available here

 

08.07.2019

Microbubbles Decorated with Dendronized Magnetic Nanoparticles for Biomedical Imaging. Effective Stabilization via Fluorous Interactions

In Beilstein Archives

Dendrons fitted with three oligoethylene glycol (OEG) chains, one of which carrying a fluorinated or hydrogenated end group, and bearing a bisphosphonate polar head (CnX2n+1OEG8Den, X = F or H; n= 2 or 4) were synthesized and grafted on the surface of iron oxide nanoparticles (IONPs) for microbubble-mediated imaging and therapeutic purposes. The size and stability of the dendronized IONPs (IONP@CnX2n+1OEG8Den) in aqueous dispersions were monitored by dynamic light scattering. Investigation of the spontaneous adsorption of IONP@CnX2n+1OEG8Den at the interface between air – or air saturated with perfluorohexane – and an aqueous phase establishes that exposure to the fluorocarbon gas markedly increases the rate of adsorption of the dendronized IONPs to the gas/water interface and decreases the equilibrium interfacial tension. This suggests that fluorous interactions are at play between the supernatant fluorocarbon gas and the fluorinated end groups of the dendrons. Furthermore, small, stable perfluorohexane-stabilized microbubbles (MBs) with a dipalmitoylphosphatidylcholine (DPPC) shell that incorporates IONP@CnX2n+1OEG8Den (DPPC/Fe molar ratio 28:1) were prepared and characterized using both optical microscopy and an acoustical method of size determination. The dendrons fitted with fluorinated end groups lead to smaller and more stable MBs than those fitted with hydrogenated groups. The most effective result is already obtained with C2F5, for which MBs, ~1.0mm in radius, reach a half-life of ~6.0 h. An atomic force microscopy investigation of spin-coated mixed films of DPPC/IONP@C2X5OEG8Den combinations (molar ratio 28:1) shows that the IONPs grafted with the fluorinated dendrons are located within the phospholipid film, while those grafted with the hydrocarbon dendrons are completely absent from the phospholipid film.

Da Shi, Justine Wallyn, Dinh-Vu Nguyen, Francis Perton, Delphine Felder-Flesch, Sylvie Bégin-Colin, Mounir Maaloum and Marie Pierre Krafft

Publication available here

 

03.07.2019

Dendron based antifouling, MRI and magnetic hyperthermia properties of different shaped iron oxide nanoparticles

In Nanotechnology

Owing to the great potential of iron oxide nanoparticles (NPs) for nanomedicine, large efforts have been made to better control their magnetic properties, especially their magnetic anisotropy to provide NPs able to combine imaging by MRI and therapy by magnetic hyperthermia. In that context, the design of anisotropic NPs appears as a very promising and efficient strategy. Furthermore, their bioactive coating also remains a challenge as it should provide colloidal stability, biocompatibility, furtivity along with good water diffusion for MRI. By taking advantage of our controlled synthesis method of iron oxide NPs with different shapes (cubic, spherical, octopod and nanoplate), we demonstrate here that the dendron coating, shown previously to be very suitable for 10 nm sized iron oxide, also provided very good colloidal, MRI and antifouling properties to the anisotropic shaped NPs. These antifouling properties, demonstrated through several experiments and characterizations, are very promising to achieve specific targeting of disease tissues without affecting healthy organs. On the other hand, the magnetic hyperthermia properties were shown to depend on the saturation magnetization and the ability of NPs to self-align, confirming the need of a balance between crystalline and dipolar magnetic anisotropies.

Cotin G, Blanco-Andujar C, Nguyen DV, Affolter C, Boutry S, Boos A, Ronot P, Uring-Lambert B, Choquet P, Zorn PE, Mertz D, Laurent S, Muller RN, Meyer F, Felder Flesch D, Begin-Colin S

Publication available here

 

22.06.2019

Stability of PMMA-grafted/Ti hybrid biomaterial interface in corrosive media

In Pure and Applied Chemistry

The stability of interfaces between polymethyl methacrylate (PMMA) and titanium (Ti) are tested in a Ringer solution that is an aggressive medium usually used for biomaterial evaluation. The devices are PMMA-grafted/Ti elaborated via a “grafting-from” method involving three steps, the alkali activation of Ti sheets, their functionalization with an initiator of polymerization through a phosphonate anchoring group and the growth of PMMA brushes. Electrochemical characterizations demonstrate that the stability of the PMMA-grafted/Ti interface in biological medium is satisfactory and that the grafting of PMMA is even acting as a protective barrier for titanium. Indeed, PMMA-grafted/Ti remains passive in Ringer solution until at least +3 V/SCE (saturated calomel electrode), even under inflammatory conditions, while localized corrosion was measured on as-received titanium in similar conditions. This protecting role is attributed to the grafted interface, since spin-coated PMMA does not decrease the corrosion sensitivity of titanium.

Tiphaine Schott,Françoise Liautaud, Sebastien Kriegel, Jacques Faerber, Wenjia He, Patrick Masson,Geneviève Pourroy, Adele Carradò

Publication available here

 

14.06.2019

How alkali-activated Ti surfaces affect the growth of tethered PMMA chains: a close-up study on the PMMA thickness and surface morphology

In Pure and Applied Chemistry

The alkali-activation of titanium (Ti) surfaces performed in a heated sodium hydroxide (NaOH) aqueous solution, results in a porous layer rich in hydroxyl (OH) groups, the structure and porosity of which strongly depend on the reaction time and NaOH concentration used. In this study, a polymerization initiator is covalently grafted on the alkali-activated Ti substrates by using a phosphonic acid as coupling agent and the resulting surfaces are used as scaffolds to drive the growth of tethered poly(methyl methacrylate) (PMMA) chains via a surface initiated atom transfer radical polymerisation (SI-ATRP). A close-up investigation of how different treatment times (1 h, 3 h, 6 h, 12 h, and 24 h) and NaOH concentrations (0.1 M, 0.5 M, 1 M, 2 M, and 5 M) affect the final PMMA morphology and thickness are presented.

Melania Reggente,Sebastien Kriegel, Wenjia He, Patrick Masson, Geneviève Pourroy, Francesco  Mura, Jacques Faerber, Daniele Passeri, Marco Rossi, Heinz Palkowski, Adele Carradò

Publication available here

 

06.06.2019

Is small smarter? Nanomaterial-based detection and elimination of circulating tumor cells: current knowledge and perspectives

In International Journal of Nanomedicine

Circulating tumor cells (CTCs) are disseminated cancer cells. The occurrence and circulation of CTCs seem key for metastasis, still the major cause of cancer-associated deaths. As such, CTCs are investigated as predictive biomarkers. However, due to their rarity and heterogeneous biology, CTCs’ practical use has not made it into the clinical routine. Clearly, methods for the effective isolation and reliable detection of CTCs are urgently needed. With the development of nanotechnology, various nanosystems for CTC isolation and enrichment and CTC-targeted cancer therapy have been designed. Here, we summarize the relationship between CTCs and tumor metastasis, and describe CTCs’ unique properties hampering their effective enrichment. We comment on nanotechnology-based systems for CTC isolation and recent achievements in microfluidics and lab-on-a-chip technologies. We discuss recent advances in CTC-targeted cancer therapy exploiting the unique properties of nanomaterials. We conclude by introducing developments in CTC-directed nanosystems and other advanced technologies currently in (pre)clinical research.

Alena Gribko, Julian Künzel, Désirée Wünsch, Qiang Lu, Sophie Madeleine Nagel, Shirley K. Knauer, Roland H. Stauber, Guo-Bin Ding

Publication available here

 

13.05.2019

Influence of Perfluorohexane‐Enriched Atmosphere on Viscoelasticity and Structural Order of Self‐Assembled Semifluorinated Alkanes at the Air‐Water Interface

In ChemPhysChem

Semifluorinated alkanes FnHm self‐assemble into nanometer‐sized surface micelles at the air‐water interface. In this study, we investigated how an atmosphere enriched with perfluorohexane (PFH) influences the interfacial viscoelasticity and structural order of a monolayer of FnHm by the combination of dilational rheology and grazing‐incidence small‐angle X‐ray scattering (GISAXS). The monolayers behaved predominantly elastic which can be attributed to the strong dipole repulsions of the surface domains. Enrichment of the atmosphere with PFH lead to an increase of the compressibility and a decrease of the elastic modulus without altering the structural ordering of the FnHm molecules into highly correlated nanodomains, suggesting the adsorption of PFH molecules to the free spaces between the domains. The capability of FnHm domains to retain the structural integrity in the presence of PFH gas is promising for the fabrication of stable microbubbles for sonographic imaging.

Salomé Mielke, Dr. Wasim Abuillan, Dr. Mariam Veschgini, Dr. Xianhe Liu, Dr. Oleg Konovalov, Prof. Dr. Marie Pierre Krafft, Prof. Dr. Motomu Tanaka

Publication available here

 

20.12.2018

Long-Range Lateral Correlation between Self-Assembled
Domains of Fluorocarbon-Hydrocarbon Tetrablocks by
Quantitative GISAXS

In ChemPhysChem

The structure and lateral correlation of fluorocarbon‐hydrocarbon tetrablock di(F10Hm) domains at the air/water interface have been determined by quantitative analysis of grazing incidence small‐angle X‐ray scattering (GISAXS) data. The measured GISAXS signals can be well represented by the full calculation of the form and structure factors. The form factor suggests that di(F10Hm) domains take a hemiellipsoid shape. Both major and minor axes of the hemiellipsoids monotonically increased in response to the elongation of the hydrocarbon blocks, which can be explained by the concominant increase in van der Waals interaction. The structure factor calculated from the GISAXS signals suggests that the domains take an orthorhombic lattice. Remarkably, the lateral correlation can reach over a distance that is more than 14 times longer than the distance to the nearest neighbors. Our data suggest that quantitative GISAXS enables the optimal design of mesoscopic self‐assemblies at the air/water interface by fine‐tuning of the structures of molecular building blocks.

Dr. Wasim Abuillan, Dr. Mariam Veschgini, Salomé Mielke, Dr. Akihisa Yamamoto, Xianhe Liu, Dr. Oleg Konovalov, Prof. Dr. Marie Pierre Krafft, Prof. Dr. Motomu Tanaka

Publication available here

 

18.12.2018

Resistance to Nano-Based Antifungals Is Mediated by Biomolecule Coronas

In ACS Applied Materials & Interfaces

Fungal infections are a growing global health and agricultural threat, and current chemical antifungals may induce various side-effects. Thus, nanoparticles are investigated as potential novel antifungals. We report that nanoparticles’ antifungal activity strongly depends on their binding to fungal spores, focusing on the clinically important fungal pathogen Aspergillus fumigatus as well as common plant pathogens, such as Botrytis cinerea. We show that nanoparticlespore complex formation was enhanced by the small nanoparticle size rather than the material, shape or charge, and could not be prevented by steric surface modifications. Fungal resistance to metal-based nanoparticles, such as ZnO-, Ag-, or CuO-nanoparticles as well as dissolution-resistant quantum dots, was mediated by biomolecule coronas acquired in pathophysiological and ecological environments, including the lung surfactant, plasma or complex organic matters.
Mechanistically, dose-dependent corona-mediated resistance occurred via reducing physical adsorption of nanoparticles to fungal spores. The inhibitory effect of biomolecules on the antifungal activity of Ag-nanoparticles was further verified in vivo, using the invertebrate Galleria mellonella as an A. fumigatus infection model. Our results explain why current nanoantifungals often show low activity in realistic application environments, and will guide nanomaterial designs that maximize functionality and safe translatability as potent antifungals for human health, biotechnology, and agriculture.

Svenja Siemer, Dana Westmeier, Cecilia Vallet, Sven Becker, Jens Voskuhl, Guo-Bin Ding, Eckhard Thines, Roland H. Stauber, Shirley K. Knauer

Publication available here

 

14.12.2018

Fluorocarbon Exposure Mode Markedly Affects Phospholipid Monolayer Behavior at the Gas/Liquid Interface: Impact on Size and Stability of Microbubbles

In Langmuir

Although most phospholipid-shelled microbubbles (MBs) investigated for medical applications are stabilized by a fluorocarbon (FC) gas, information on the interactions between the phospholipid and FC molecules at the gas/water interface remains scarce. We report that the procedure of introduction of perfluorohexane (F-hexane), that is, either in the gas phase above dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) Langmuir monolayers, or in the aqueous subphase, radically affects the compression isotherms. When introduced in the gas phase, F-hexane is rapidly incorporated in the interfacial film, but is also readily desorbed upon compression and eventually totally expelled from the phospholipid monolayers. By contrast, when introduced in the aqueous phase, F-hexane remains trapped at the interface. These dissimilar outcomes demonstrate that the phospholipid monolayer acts as a barrier that effectively hinders the transfer of the FC across the interfacial film. F-hexane was also found to significantly accelerate the adsorption kinetics of the phospholipids at the gas/water interface and to lower the interfacial tension, as assessed by bubble profile analysis tensiometry. The extent of these effects is more pronounced when F-hexane is provided from the gas phase. The size and stability characteristics of DMPC- and DPPC-shelled microbubbles were also found to depend on how the FC is introduced. As compared to reference MBs prepared under nitrogen only, introduction of F-hexane always causes a decrease in MB mean radius. However, while for DMPC this decrease depends on the F-hexane introduction procedure, it is independent from the procedure and most pronounced (from ∼2.0 μm to ∼1.0 μm) for DPPC. Introducing the FC in the gas phase has the strongest effect on MB half-life (t1/2 = ∼1.8 and 6.8 h for DMPC and DPPC, respectively), as compared to when it is delivered through the aqueous phase (∼0.8 and ∼1.7 h). Fluorocarbonless reference DMPC and DPPC bubbles had a half-life of ∼0.5 and 0.8 h, respectively. The effects of F-hexane on MB characteristics are discussed with regard to the interactions between phospholipids and F-hexane and monolayer fluidization effect, as revealed by the Langmuir and tensiometric studies.

Da Shi, Xianhe Liu, Claire Counil, Marie Pierre Krafft

Publication available here

 

14.12.2018

Macrophage functionality and homeostasis in response to oligoethyleneglycol-coated IONPs: impact of a dendritic architecture

In International Journal of Pharmaceutics

The engineering of iron oxide nanoparticles (IONPs) for biomedical use has received great interest over the past decade. In the present study we investigated the biocompatibility of IONPs grafted with linear (2P) or generation 1 (2PG1) or 2 (2PG2) dendronized oligoethyleneglycol units in THP-1-derived macrophages. To evaluate IONP effects on cell functionality and homeostasis, mitochondrial function (MTT assay), membrane permeability (LDH release), inflammation (IL-8), oxidative stress (reduced glutathione, GSH), NLRP3-inflammasome activation (IL-1β) and nanoparticle cellular uptake (intracellular iron content) were quantified after a 4-h or 24-h cell exposure to increasing IONP concentrations (0-300 µg Fe/mL). IONPs coated with a linear molecule, NP10COP@2P, were highly taken up by cells and induced significant dose-dependent IL-8 release, oxidative stress and NLRP3 inflammasome activation. In comparison, IONPs coated with dendrons of generation 1 (NP10COP@2PG1) and 2 (NP10COP@2PG2) exhibited better biocompatibility. Effect of the dendritic architecture of the surface coating was investigated in a kinetic experiment involving cell short-term exposure (30 min or 1h30) to the two dendronized IONPs. NP10COP@2PG2 disrupted cellular homeostasis (LDH release, IL-1β and IL-8 secretion) to a greater extend than NP10COP@2PG1, which makes this last IONP the best candidate as MRI contrast or theranostic agent.

Anne Casset, Julien Jouhannaud, Antonio Garofalo, Coralie Spiegelhalter, Dinh-Vu Nguyen, Delphine Felder-Flesch, Geneviève Pourroy, Françoise Pons

Publication available here

 

04.12.2018

Nanosized food additives impact beneficial and pathogenic bacteria in the human gut: a simulated gastrointestinal study

In NPJ Science of Food

Nanotechnology provides the food industry with new ways to modulate various aspects of food. Hence, engineered nanoparticles (NPs) are increasingly added to food and beverage products as functional ingredients. However, the impact of engineered as well as naturally occurring NPs on both commensal and pathogenic microorganisms within the gastrointestinal tract (GI) is not fully understood. Here, well-defined synthetic NPs and bacterial models were used to probe nanoparticle–bacteria interactions, from analytical to in situ to in vitro. NP–bacteria complexation occurred most efficiently for small NPs, independent of their core material or surface charge, but could be reduced by NPs’ steric surface modifications. Adsorption to bacteria could also be demonstrated for naturally occurring carbon NPs isolated from beer. Complex formation affected the (patho)biological behavior of both the NPs and bacteria, including their cellular uptake into epithelial cells and phagocytes, pathogenic signaling pathways, and NP-induced cell toxicity. NP–bacteria complex formation was concentration-dependently reduced when the NPs became coated with biomolecule coronas with sequential simulation of first oral uptake and then the GI. However, efficient NP adsorption was restored when the pH was sufficiently low, such as in simulating the conditions of the stomach. Collectively, NP binding to enteric bacteria may impact their (patho)biology, particularly in the stomach. Nanosized-food additives as well as naturally occurring NPs may be exploited to (rationally) shape the microbiome. The information contained in this article should facilitate a “safe by design” strategy for the development and application of engineered NPs as functional foods ingredients.

Svenja Siemer, Angelina Hahlbrock, Cecilia Vallet, David Julian McClements, Jan Balszuweit, Jens Voskuhl, Dominic Docter, Silja Wessler, Shirley K. Knauer, Dana Westmeier & Roland H. Stauber

Publication available here

 

02.12.2018

Breaking resistance to nanoantibiotics by overriding corona-dependent inhibition using a pH-switch

In Materials Today

Nanoparticles are investigated as novel antibiotics, but are often inefficient in practical applications. We show from in situ to in vitro to in vivo that the bactericidal activity of metal-based nanoparticles but not microparticles against multidrug-resistant clinical isolates (MDR) strongly depends on physical binding to pathogens. Using controllable nanoparticle models, we report that nanoparticle–bacteria complex formation was enhanced by small nanoparticle size rather than material or charge. However, nanoparticles‘ binding and thus antibiotic activity were concentration-dependently reduced by biomolecule coronas, acquired in pathophysiological environments, such as wounds or blood, causing bacterial resistance. Complex formation and MDR killing could however be restored by low-pH nanoparticle formulations, breaking bacterial resistance. Mechanistically, interaction of negatively charged, human plasma corona-covered, metal-based nanoparticles with pathogends was electrostatically enhanced by lowering pH-dependently bacteria’s negative surface charge. Using two independent in vivo models, Galleria mellonella and mice, low pH-induced complex formation was critical to significantly inhibit MDR Staphylococcus aureus skin wound infections by silver nanoparticles. We here identified the first resistance mechanism specific for nanoantibiotics, provide an explanation why nanoantibiotics show reduced activity in clinically relevant environments, and a simple though effective way to boost nanoantibiotics’ bactericidal activity for practical applications.

In this work, we demonstrate that nanoantibiotics’ activity depends on their binding to pathogens. Low pH NP-formulations electrostatically enhance complex formation, overriding the inhibitory impact of biomolecule coronas relevant for practical applications. We illustrate, which environmental factors influence NP–pathogen interaction. At pH <7, the pathogens‘ negative surface charge is lowered due to protonation of surface molecules, increasing electrostatic interactions of corona-covered NPs with bacterial surfaces.

 

 

 

 

 

 

 

 

 

Svenja Siemer, Dana Westmeier, Cecilia Vallet, Jörg Steinmann, Jan Buer, Roland H. Stauber, Shirley K. Knauer

Publication available here

 

21.11.2018

Biomolecule-corona formation confers resistance of bacteria to nanoparticleinduced
killing: Implications for the design of improved nanoantibiotics

In Biomaterials

Multidrug-resistant bacterial infections are a global health threat. Nanoparticles are thus investigated as novel antibacterial agents for clinical practice, including wound dressings and implants. We report that nanoparticles‘ bactericidal activity strongly depends on their physical binding to pathogens, including multidrug-resistant primary clinical isolates, such as Staphylococcus aureus, Klebsiella pneumoniae or Enterococcus faecalis. Using controllable nanoparticle models, we found that nanoparticle-pathogen complex formation was enhanced by small nanoparticle size rather than material or charge, and was prevented by ’stealth‘ modifications. Nanoparticles seem to preferentially bind to Gram-positive pathogens, such as Listeria monocytogenes, S. aureus or Streptococcus pyrogenes, correlating with enhanced antibacterial activity. Bacterial resistance to metal-based nanoparticles was mediated by biomolecule coronas acquired in pathophysiological environments, such as wounds, the lung, or the blood system. Biomolecule corona formation reduced nanoparticles‘ binding to pathogens, but did not impact nanoparticle dissolution. Our results provide a mechanistic explanation why nanosized antibiotics may show reduced activity in clinically relevant environments, and may inspire future nanoantibiotic designs with improved and potentially pathogen-specific activity.

Svenja Siemer, Dana Westmeier, Matthias Barz, Jonas Eckrich, Désirée Wünsch, Christof Seckert, Christian Thyssen, Oliver Schilling, Mike Hasenberg, Chengfang Pang, Dominic Docter, Shirley K. Knauer, Roland H. Stauber, Sebastian Strieth

Publication available here

 

29.10.2018

Unravelling the Thermal Decomposition Parameters for The Synthesis of Anisotropic Iron Oxide Nanoparticles

In Nanomaterials

Iron oxide nanoparticles are widely used as a contrast agent in magnetic resonance imaging (MRI), and may be used as therapeutic agent for magnetic hyperthermia if they display in particular high magnetic anisotropy. Considering the effect of nanoparticles shape on anisotropy, a reproducible shape control of nanoparticles is a current synthesis challenge. By investigating reaction parameters, such as the iron precursor structure, its water content, but also the amount of the surfactant (sodium oleate) reported to control the shape, iron oxide nanoparticles with different shape and composition were obtained, in particular, iron oxide nanoplates. The effect of the surfactant coming from precursor was taking into account by using in house iron stearates bearing either two or three stearate chains and the negative effect of water on shape was confirmed by considering these precursors after their dehydration. Iron stearates with three chains in presence of a ratio sodium oleate/oleic acid 1:1 led mainly to nanocubes presenting a core-shell Fe1−xO@Fe3−xO4 composition. Nanocubes with straight faces were only obtained with dehydrated precursors. Meanwhile, iron stearates with two chains led preferentially to the formation of nanoplates with a ratio sodium oleate/oleic acid 4:1. The rarely reported flat shape of the plates was confirmed with 3D transmission electronic microscopy (TEM) tomography. The investigation of the synthesis mechanisms confirmed the major role of chelating ligand and of the heating rate to drive the cubic shape of nanoparticles and showed that the nanoplate formation would depend mainly on the nucleation step and possibly on the presence of a given ratio of oleic acid and chelating ligand (oleate and/or stearate).

Geoffrey Cotin, Céline Kiefer, Francis Perton, Dris Ihiawakrim, Cristina Blanco-Andujar, Simona Moldovan, Christophe Lefevre, Ovidiu Ersen, Benoit Pichon, Damien Mertz and Sylvie Bégin-Colin

Publication available here

 

28.09.2018

Nonlinear Viscoelasticity of Highly Ordered, Two-Dimensional Assemblies of Metal Nanoparticles Confined at the Air/Water Interface

In Langmuir

In this study, we investigated the viscoelastic properties of metal nanoparticle monolayers at the air/water interface by dilational rheology under periodic oscillation of surface area. Au nanoparticles capped with oleylamine form a stable, dense monolayer on a Langmuir film balance. The stress response function of a nanoparticle monolayer was first analyzed using the classical Kelvin–Voigt model, yielding the spring constant and viscosity. The obtained results suggest that the monolayer of nanoparticles is predominantly elastic, forming a two-dimensional physical gel. As the global shape of the signal exhibited a clear nonlinearity, we further analyzed the data with the higher modes in the Fourier series expansion. The imaginary part of the higher mode signal was stronger than the real part, suggesting that the dissipative term mainly causes the nonlinearity. Intriguingly, the response function measured at larger strain amplitude became asymmetric, accompanied by the emergence of even modes. The significance of interactions between nanoparticles was quantitatively assessed by calculating the potential of mean force, indicating that the lateral correlation could reach up to the distance much larger than the particle diameter. The influence of surface chemical functions and core metal has also been examined by using Au nanoparticles capped with partially fluorinated alkanethiolate and Ag nanoparticles capped with myristic acid. The combination of dilational rheology and correlation analyses can help us precisely control two-dimensional colloidal assembly of metal nanoparticles with fine-adjustable localized surface plasmon resonance.

 

Shihomi Masuda, Salomé Mielke, Federico Amadei, Akihisa Yamamoto, Pangpang Wang, Takashi Taniguchi, Kenichi Yoshikawa, Kaoru Tamada, Motomu Tanaka

Publication available here

 

16.07.2018

Evaluating the Critical Roles of Precursor Nature and Water Content When Tailoring Magnetic Nanoparticles for Specific Applications

In ACS Appl. Nano Mater.

Because of the broad range of application of iron oxide nanoparticles (NPs), the control of their size and shape on demand remains a great challenge, as these parameters are of upmost importance to provide NPs with magnetic properties tailored to the targeted application. One promising synthesis process to tune their size and shape is the thermal decomposition one, for which a lot of parameters were investigated. But two crucial issues were scarcely addressed: the precursor’s nature and water content. Two in house iron stearates with two or three stearate chains were synthesized, dehydrated, and then tested in standard synthesis conditions of spherical and cubic NPs. Investigations combined with modeling showed that the precursor’s nature and hydration rate strongly affect the thermal decomposition kinetics and yields, which, in turn, influence the NP size. The cubic shape depends on the decomposition kinetics but also crucially on the water content. A microscopic insight was provided by first-principles simulation showing an iron reduction along the reaction pathway and a participation of water molecules to the building unit formation.

 

 

 

 

 

 

 

 

Geoffrey Cotin, Céline Kiefer, Francis Perton, Mauro Boero, Burak Özdamar, Assil Bouzid, Guido
Ori, Carlo Massobrio, Dominique Begin, Benoit P. Pichon, Damien Mertz, and Sylvie Begin-Colin

Publication available here

 

16.07.2018

Small Meets Smaller: Effects of Nanomaterials on Microbial Biology, Pathology, and Ecology

In ACS Nano

As functionalities and levels of complexity in nanomaterials have increased, unprecedented control over microbes has been enabled, as well. In addition to being pathogens and relevant to the human microbiome, microbes are key players for sustainable biotechnology. To overcome current constraints, mechanistic understanding of nanomaterials’ physicochemical characteristics and parameters at the nano–bio interface affecting nanomaterial–microbe crosstalk is required. In this Perspective, we describe key nanomaterial parameters and biological outputs that enable controllable microbe–nanomaterial interactions while minimizing design complexity. We discuss the role of biomolecule coronas, including the problem of nanoantibiotic resistance, and speculate on the effects of nanomaterial–microbe complex formation on the outcomes and fates of microbial pathogens. We close by summarizing our current knowledge and noting areas that require further exploration to overcome current limitations for next-generation practical applications of nanotechnology in medicine and agriculture.

 

 

 

 

 

 

 

Roland H. Stauber, Svenja Siemer, Sven Becker, Guo-Bin Ding, Sebastian Strieth and Shirley K. Knauer

Publication available here

 

04.07.2018

Changing environments and biomolecule coronas: consequences and challenges for the design of environmentally acceptable engineered nanoparticles

In Green Chemistry RSC

Nanomaterials (NMs) are gaining increasing commercial importance due to a variety of properties that cannot be achieved with bulk materials. Yet the assessment of their environmental impacts lags behind the technological development. First attempts towards designing inherently safer NMs have been made, yet we are still unable to formulate rules of green nano-design, especially in terms of mitigating (long-term) toxicity and bioaccumulation. Importantly, NMs released to the environment acquire a so called ‘environmental corona’ – a complex layer of spontaneously adsorbed biomolecules – that significantly impacts their behaviour and fate. This review integrates the current literature on the impact of environmental conditions on NMs fate and behaviour, including corona formation, colloidal stability, reactivity, and toxicty, using a broad range of environmentally relevant NMs. Collectively, components of natural waters (such as salts and/or natural organic matter) often mitigate negative impacts of NMs via different mechanisms including surface passivation and stabilisation against dissolution. The review concludes by discussing some initial strategies on how to rationally design more environmentally acceptable NMs.

Marta Markiewicz, Jolanta Kumirska, Iseult Lynch, Marianne Matzke, Jan Köser, Steve Bemowsky, Dominic Docter, Roland Stauber, Dana Westmeier, Stefan Stolte

 

 

20.06.2018

Nanoparticle decoration impacts airborne fungal pathobiology

In PNAS

Airborne fungal pathogens, predominantly Aspergillus fumigatus, can cause severe respiratory tract diseases. Here we show that in environments, fungal spores can already be decorated with nanoparticles. Using representative controlled nanoparticle models, we demonstrate that various nanoparticles, but not microparticles, rapidly and stably associate with spores, without specific functionalization. Nanoparticle-spore complex formation was enhanced by small nanoparticle size rather than by material, charge, or “stealth” modifications and was concentration-dependently reduced by the formation of environmental or physiological biomolecule coronas. Assembly of nanoparticle-spore surface hybrid structures affected their pathobiology, including reduced sensitivity against defensins, uptake into phagocytes, lung cell toxicity, and TLR/cytokine-mediated inflammatory responses. Following infection of mice, nanoparticle-spore complexes were detectable in the lung and less efficiently eliminated by the pulmonary immune defense, thereby enhancing A. fumigatus infections in immunocompromised animals. Collectively, self-assembly of nanoparticle-fungal complexes affects their (patho)biological identity, which may impact human health and ecology.

Dana Westmeier, Djamschid Solouk-Saran, Cecilia Vallet, Svenja Siemer, Dominic Docter, Hermann Götz, Linda Männ, Anja Hasenberg, Angelina Hahlbrock, Kathrin Erler, Christoph Reinhardt, Oliver Schilling, Sven Becker, Matthias Gunzer, Mike Hasenberg, Shirley K. Knauer, and Roland H. Stauber

Publication available here

 

17.05.2018

Nanomaterial–microbe cross-talk: physicochemical principles and (patho)biological consequences

In Chemical Society Reviews

The applications of nanoparticles (NPs) are increasing exponentially in consumer products, biotechnology and biomedicine, and humans, as well as the environment, are increasingly being exposed to NPs. Analogously, various (pathogenic) microorganisms are present at all the major exposure and entry sites for NPs in the human body as well as in environmental habitats. However, the field has just started to explore the complex interplay between NPs and microbes and the (patho)biological consequences. Based on recent insights, herein, we critically reviewed the available knowledge about the interaction of NPs with microbes and the analytical investigations including the latest intravital imaging tools. We have commented on how the NPs’ characteristics influence complex formation with microorganisms, presented the underlying physicochemical forces, and provided examples of how this knowledge can be used to rationally control the NP–microbe interaction. We concluded by discussing the role of the biomolecule corona in NP–microbe crosstalk and speculated the impact of NP–microbe complex formation on the (patho)biological outcome and fate of microbial pathogens. The presented insights will not only support the field in engineering NPs with improved anti-microbial activity but also stimulate research on the biomedical and toxicological relevance of nanomaterial–microbiome complex formation for the anthropocene in general.

Graphical abstract: Nanomaterial–microbe cross-talk: physicochemical principles and (patho)biological consequences
D. Westmeier, A. Hahlbrock, C. Reinhardt, J. Fröhlich-Nowoisky, S. Wessler, C. Vallet, U. Pöschl, S. K. Knauer and R. H. Stauber

 

23.04.2018

Expressional analysis of diseaserelevant signalling-pathways in primary tumours and metastasis of head and neck cancers

In Scientific Reports – Nature

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC.

Dorothee Goesswein, Negusse Habtemichael, Aslihan Gerhold-Ay, Johanna Mazur,
Désirée Wünsch, Shirley K. Knauer, Julian Künzel, Christoph Matthias, Sebastian Strieth
& Roland H. Stauber

Publication available here

 

17.01.2018

Novel Alkali Activation of Titanium Substrates To Grow Thick and Covalently Bound PMMA Layers

In ACS Applied Materials & Interfaces

Titanium (Ti) is the most widely used metal in biomedical applications because of its biocompatibility; however, the significant difference in the mechanical properties between Ti and the surrounding tissues results in stress shielding which is detrimental for load-bearing tissues. In the current study, to attenuate the stress shielding effect, a new processing route was developed. It aimed at growing thick poly(methyl methacrylate) (PMMA) layers grafted on Ti substrates to incorporate a polymer component on Ti implants. However, the currently available methods do not allow the development of thick polymeric layers, reducing significantly their potential uses. The proposed route consists of an alkali activation of Ti substrates followed by a surface-initiated atom transfer radical polymerization using a phosphonic acid derivative as a coupling agent and a polymerization initiator and malononitrile as a polymerization activator. The average thickness of the grown PMMA layers is approximately 1.9 μm. The Ti activation—performed in a NaOH solution—leads to a porous sodium titanate interlayer with a hierarchical structure and an open microporosity. It promotes the covalent grafting reaction because of high hydroxyl groups’ content and enables establishing a further mechanical interlocking between the growing PMMA layer and the Ti substrate. As a result, the produced graduated structure possesses high Ti/PMMA adhesion strength (∼260 MPa). Moreover, the PMMA layer is (i) thicker compared to those obtained with the previously reported techniques (∼1.9 μm), (ii) stable in a simulated body fluid solution, and (iii) biocompatible. This strategy opens new opportunities toward hybrid prosthesis with adjustable mechanical properties with respect to host bone properties for personalized medicines.

Melania Reggente, Patrick Masson, Camille Dollinger, Heinz Palkowski, Spyridon Zafeiratos, Leandro Jacomine, Daniele Passeri, Marco Rossi, Nihal Engin Vrana, Geneviève Pourroy and Adele Carradò

 

Publication available here

 

04.01.2018

Evaluation of the Active Targeting of Melanin Granules after Intravenous Injection of Dendronized Nanoparticles

In Molecular Pharmaceutics

The biodistribution of dendronized iron oxides, NPs10@D1_DOTAGA and melanin-targeting NPs10@D1_ICF_DOTAGA, was studied in vivo using magnetic resonance imaging (MRI) and planar scintigraphy through [177Lu]Lu-radiolabeling. MRI experiments showed high contrast power of both dendronized nanoparticles (DPs) and hepatobiliary and urinary excretions. Little tumor uptake could be highlighted after intravenous injection probably as a consequence of the negatively charged DOTAGA-derivatized shell, which reduces the diffusion across the cells’ membrane. Planar scintigraphy images demonstrated a moderate specific tumor uptake of melanoma-targeted [177Lu]Lu-NPs10@D1_ICF_DOTAGA at 2 h post-intravenous injection (pi), and the highest tumor uptake of the control probe [177Lu]Lu-NPs10@D1_DOTAGA at 30 min pi, probably due to the enhanced permeability and retention effect. In addition, ex vivo confocal microscopy studies showed a high specific targeting of human melanoma samples impregnated with NPs10@D1_ICF_Alexa647_ DOTAGA.

Catalina Bordeianu, Audrey Parat, Sébastien Piant, Aurélie Walter, Christine Zbaraszczuk-Affolter, Florent Meyer, Sylvie Begin-Colin, Sébastien Boutry, Robert N. Muller, Elodie Jouberton, Jean-Michel Chezal, Bruno Labeille, Elisa Cinotti, Jean-Luc Perrot, Elisabeth Miot-Noirault, Sophie Laurent, and Delphine Felder-Flesch

Publication available here

 

05.12.2017

Nanoparticle binding attenuates the pathobiology
of gastric cancer-associated Helicobacter pylori

In Nanoscale

Enteric bacteria may cause severe diseases, including gastric cancer-associated Helicobacter pylori. Their infection paths overlap with the oro-gastrointestinal uptake route for nanoparticles, increasingly occurring during environmental or consumer/medical exposure. By comprehensive independent analytical methods, such as live cell fluorescence, electron as well as atomic force microscopy and elemental analysis, we show that a wide array of nanoparticles (NPs) but not microparticles form complexes with H. pylori and enteric pathogens without the need for specific functionalization. The NP-assembly that occurred rapidly was not influenced by variations in physiological temperature, though affected by the NPs’ physico-chemical characteristics. Improved binding was observed for small NPs with a negative surface charge, whereas binding could be reduced by surface ‘stealth’ modifications. Employing human gastric epithelial cells and 3D-organoid models of the stomach, we show that NP-coating did not inhibit H. pylori’s cellular attachment. However, even the assembly of non-bactericidal silica NPs attenuated H. pylori infection by reducing CagA phosphorylation, cytoskeletal rearrangement, and IL-8 secretion. Here we demonstrate that NP binding to enteric bacteria may impact their pathobiology which could be further exploited to rationally modulate the (patho)biology of microbes by nanomaterials.

Dana Westmeier, Gernot Posselt, Angelina Hahlbrock, Sina Bartfeld, Cecilia Vallet, Carmen Abfalter, Dominic Docter, Shirley K. Knauer, Silja Wessler and Roland H. Stauber

Publication available here

 

05.11.2017

Multiscale mechanical characterization of hybrid Ti/PMMA layered materials

In Colloids and Surfaces A: Physicochemical and Engineering Aspects

Metal surfaces coated with organic layers are innovative materials with high potential for many industrial applications. To overcome the limitations due to the generally poor adhesion between these two components, polymers covalently anchored onto the substrate (‘grafted’ polymers) have been proposed as adhesives interlayers. Their mechanical properties, however, strongly affect their performances and thus have to be characterized at different scales. In this paper we report the mechanical characterization of thick poly(methyl methacrylate) (PMMA) layers grafted on titanium substrates using standard nanoindentation as well as different AFM-based techniques, namely AFM-based nanoindentation, contact resonance AFM (CR-AFM), HarmoniX™, and PeakForce quantitative nanomechanical mapping (PF-QNM™). The specific results obtained with each technique reflect the mechanical properties at different scales for these multiscale systems. Thus, these methods constitute a unique set of techniques for the complete analysis of the mechanical response of advanced materials from the macro- down to the nanoscale.

M.Reggente,M.Natali,D.Passeri, M.Lucci, I.Davoli, G.Pourroy, P.Masson, H.Palkowski, U.Hangen, A.Carradò, and M.Rossi

Publication available here

 

23.10.2017

2D Spherulites of a Semi-Fluorinated Alkane: Controlled
Access to Either Radial Or Ring-Banded Morphologies

In ChemPhysChem

Thin films of a semi‐fluorinated alkane cast onto solid substrates consist of well‐formed two‐dimensional non‐birefringent ring‐banded and/or radial spherulites. Controlling the experimental conditions allows orientation of the crystallization toward either radial‐only or ring‐banded‐only morphologies. Intermediate states were also captured in which both radial and ring‐banded spherulites coexist. Monitoring of the formation of these intermediate states brought evidence for a first crystallization mode that sweeps radially outwards from a central nucleus until the propagating front edge experiences a second crystallization mode that proceeds through a diffusion‐controlled rhythmic crystallization mechanism that leads to high (≈2 μm) concentric ridges. These 2D spherulites were investigated by optical and atomic force microscopies, interferometric profilometry, and off‐specular neutron scattering.

Xianhe Liu, Salomé Mielke, Christophe Contal, Damien Favier, Akihisa Yamamoto, Prof. Motomu Tanaka, Dr. Marie Pierre Krafft

Publication available here

 

26.05.2017

How a grafting anchor tailors the cellular uptake and in vivo fate of dendronized iron oxide nanoparticles

In Journal of Materials Chemistry B

Superparamagnetic spherical iron oxide nanoparticles of 10 nm diameter have been synthesized by thermal decomposition and grafted through a direct ligand exchange protocol with two dendrons bearing respectively a monophosphonic anchor (D2) or a biphosphonic tweezer (D2-2P) at their focal point. Physico-chemical characterization techniques such as dynamic light scattering (DLS), zeta potential, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID) magnetometry were used to assess their composition, colloidal stability and magnetic properties. High-resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy studies have been conducted to understand the organic shell composition and to determine both the grafting rate of the dendrons onto the nanoparticle surface and the influence of the remaining oleic acid originating from the synthesis protocol on the cellular uptake. Both dendronized IONPs showed moderate in vitro toxicity (MTT and LDH tests) in human cancer and primary cell lines. Furthermore, in vivo MRI studies showed high contrast enhancement as well as renal and hepatobiliary excretions and highlighted the influence of the grafting anchor (mono- versus bi-phosphonate) on the in vivo fate of dendronized magnetic iron oxides.