Magazine Articles |
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Piard, J., Bon, C., Jegat, C., Doré, C., Petcut, V., Montanelli, R., & Méallet-Renault, R. (2017). Thermoluminochromisme de complexes de type Cu4I4(pyridine)4. Bulletin de l’Union des Physiciens, 991, 205–224.
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Piard, J., Gatin-Fraudet, B., Grenier, A., Maujean, T., Péault, L., & Méallet-Renault, R. (2017). Thermochromisme d’un complexe de cobalt (II). Bulletin de l’Union des Physiciens, 999, 1221–1253.
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Peer-reviewed Publications |
Al Salloum, H., Saunier, J., Dazzi, A., Vigneron, J., Etcheberry, A., Marliere, C., Aymes-Chodur, C., Herry, J. M., Bernard, M., Jubeli, E., & Yagoubi, N. (2017). Characterization of the surface physico-chemistry of plasticized PVC used in blood bag and infusion tubing. Materials Science & Engineering C-Materials For Biological Applications, 75, 317–334.
Résumé: Commercial infusion tubing and blood storage devices (tubing, blood and platelets bags) made of plasticized PVC were analyzed by spectroscopic, chromatographic and microscopic techniques in order to identify and quantify the additives added to the polymer (lubricants, thermal stabilizers, plasticizers) and to put into evidence their blooming onto the surface of the devices. For all the samples, deposits were observed on the surface but with different kinds of morphologies. Ethylene bis amide lubricant and metallic stearate stabilizers were implicated in the formation of these layers. In contact with aqueous media, these insoluble deposits were damaged, suggesting a possible particulate contamination of the infused solutions. (C) 2017 Elsevier B.V. All rights reserved.
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Aykac, A., Noiray, M., Malanga, M., Agostoni, V., Casas-Solvas, J. M., Fenyvesi, E., Gref, R., & Vargas-Berenguel, A. (2017). A non-covalent “click chemistry” strategy to efficiently coat highly porous MOF nanoparticles with a stable polymeric shell. Biochimica Et Biophysica Acta-General Subjects, 1861(6), 1606–1616.
Résumé: Background: Metal-organic framework nanoparticles (nanoMOFs) are biodegradable highly porous materials with a remarkable ability to load therapeutic agents with a wide range of physico-chemical properties. Engineering the nanoMOFs surface may provide nanoparticles with higher stability, controlled release, and targeting abilities. Designing postsynthetic, non-covalent self-assembling shells for nanoMOFs is especially appealing due to their simplicity, versatility, absence of toxic byproducts and minimum impact on the original host-guest ability. Methods: In this study, several beta-cyclodextrin-based monomers and polymers appended with mannose or rhodamine were randomly phosphorylated, and tested as self-assembling coating building blocks for iron trimesate MIL-100(Fe) nanoMOFs. The shell formation and stability were studied by isothermal titration calorimetry (ITC), spectrofluorometry and confocal imaging. The effect of the coating on tritium-labeled AZT-PT drug release was estimated by scintillation counting. Results: Shell formation was conveniently achieved by soaking the nanoparticles in self-assembling agent aqueous solutions. The grafted phosphate moieties enabled a firm anchorage of the coating to the nanoMOFs. Coating stability was directly related to the density of grafted phosphate groups, and did not alter nanoMOFs morphology or drug release kinetics. Conclusion: An easy, fast and reproducible non-covalent functionalization of MIL-100(Fe) nanoMOFs surface based on the interaction between phosphate groups appended to beta-cyclodextrin derivatives and iron(III) atoms is presented. General significance: This study proved that discrete and polymeric phosphatep-cyclodextrin derivatives can conform non-covalent shells on iron(III)-based nanoMOFs. The flexibility of the beta-cyclodextrin to be decorated with different motifs open the way towards nanoMOFs modifications for drug delivery, catalysis, separation, imaging and sensing. This article is part of a Special Issue entitled “Recent Advances in Bionanomaterials” Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. (C) 2017 Elsevier B.V. All rights reserved.
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Boudjemaa, R., Briandet, R., Fontaine-Aupart, M. P., & Steenkeste, K. (2017). How do fluorescence spectroscopy and multimodal fluorescence imaging help to dissect the enhanced efficiency of the vancomycin-rifampin combination against Staphylococcus aureus infections? Photochemical & Photobiological Sciences, 16(9), 1391–1399.
Résumé: Staphylococcus aureus is one of the most frequent pathogens responsible for biofilm-associated infections. Among current clinical antibiotics, very few enable long-term successful treatment. Thus, it becomes necessary to better understand antibiotic failures and successes in treating infections in order to master the use of proper antibiotic therapies. In this context, we took benefit from a set of fluorescence spectroscopy and imaging methods, with the support of conventional microbiological tools to better understand the vancomycin-rifampin combination (in) efficiency against S. aureus biofilms. It was shown that both antibiotics interacted by forming a complex. This latter allowed a faster penetration of the drugs before dissociating from each other to interact with their respective biological targets. However, sufficiently high concentrations of free vancomycin should be maintained, either by increasing the vancomycin concentration or by applying repetitive doses of the two drugs, in order to eradicate rifampin-resistant mutants.
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Boudjemaa, R., Briandet, R., Steenkeste, K., & Fontaine-Aupart, M. - P. (2017). Taking advantage of fluorescent-based tools to puzzle out successes and failures of antibiotics to inactivate infectious bacteria. Encyclopedia of Analytical Chemistry, , 1–18.
Résumé: In microbiology, fluorescence tools have undoubtedly proven their performance to analyze in real-time, non-invasively and quantitatively, the structure, composition, processes, and dynamics of microbial communities. Importantly, the available fluorescence-based methods enable to decipher multiscale events implicated in the failures and successes of antibiotics treatments. The goal of this article is to review the large range of fluorescence techniques and probes and their interest (i) to study bacterial cells viability in vitro and in vivo under antibiotics exposure, (ii) to elucidate the mechanisms of action of these drugs, and (iii) to dissect bacterial mechanisms to resist and tolerate antibiotics action.
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Bouissou, A., Proag, A., Bourg, N., Pingris, K., Cabriel, C., Balor, S., Mangeat, T., Thibault, C., Vieu, C., Dupuis, G., Fort, E., Leveque-Fort, S., Maridonneau-Parini, I., & Poincloux, R. (2017). Podosome Force Generation Machinery: A Local Balance between Protrusion at the Core and Traction at the Ring. Acs Nano, 11(4), 4028–4040.
Résumé: Determining how cells generate and trans duce mechanical forces at the nanoscale is a major technical challenge for the understanding of numerous physiological and pathological processes. Podosomes are submicrometer cell structures with a columnar F-actin core surrounded by a ring of adhesion proteins, which possess the singular ability to protrude into and probe the extracellular matrix. Using protrusion force microscopy, we have previously shown that single podosomes produce local nanoscale protrusions on the extracellular environment. However, how cellular forces are distributed to allow this protruding mechanism is still unknown. To investigate the molecular machinery of protrusion force generation, we performed mechanical simulations and developed quantitative image analyses of nanoscale architectural and mechanical measurements. First, in silico modeling showed that the deformations of the substrate made by podosomes require protrusion forces to be balanced by local traction forces at the immediate core periphery where the adhesion ring is located. Second, we showed that three-ring proteins are required for actin polymerization and protrusion force generation. Third, using DONALD, a 3D nanoscopy technique that provides 20 nm isotropic localization precision, we related force generation to the molecular extension of talin within the podosome ring, which requires vinculin and paxillin, indicating that the ring sustains mechanical tension. Our work demonstrates that the ring is a site of tension, balancing protrusion at the core. This local coupling of opposing forces forms the basis of protrusion and reveals the podosome as a nanoscale autonomous force generator.
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Chan, A. J., Sarkar, P., Gaboriaud, F., Fontaine-Aupart, M. P., & Marliere, C. (2017). Control of interface interactions between natural rubber and solid surfaces through charge effects: an AFM study in force spectroscopic mode. Rsc Advances, 7(69), 43574–43589.
Résumé: This work presents a detailed investigation of interface interactions between natural rubber (NR) particles and solid surfaces in aqueous mediumat high ionic strength (0.1 M) using AFM in fast force spectroscopy mode. In this study, an original method for fixing the NR on the substrate was developed. This avoided the usual perturbations common in standard immobilization techniques. We proved that the adhesion process of the NR is monitored by slight changes in the surface charge state of the contacting solid surfaces made of silicon oxide or silicon nitride. The results were interpreted using Dynamic Force Spectroscopy theory, with the introduction of a supplementary term describing the electrostatic energy. Furthermore, these experiments revealed that adhesion between NR and tip was time dependent in a cumulative process. In addition, an increase of the adhesion between NR and AFM tip with the size of the rubber particles was measured. This was related to the higher concentration in lipids versus proteins for larger NR particles. These results are of great importance both for practical applications in solution-based industrial processes and to the fundamental knowledge of adhesion process involved for biopolymers or living cells.
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Costa-Gouveia, J., Pancani, E., Jouny, S., Machelart, A., Delorme, V., Salzano, G., Iantomasi, R., Piveteau, C., Queval, C. J., Song, O. R., Flipo, M., Deprez, B., Saint-Andre, J. P., Hureaux, J., Majlessi, L., Willand, N., Baulard, A., Brodin, P., & Gref, R. (2017). Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. Scientific Reports, 7, 5390.
Résumé: Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered “booster” molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, “green” beta-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer (R), was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH: Booster] pair in TB chemotherapy.
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Dajkovic, A., Tesson, B., Chauhan, S., Courtin, P., Keary, R., Flores, P., Marliere, C., Filipe, S. R., Chapot-Chartier, M. P., & Carballido-Lopez, R. (2017). Hydrolysis of peptidoglycan is modulated by amidation of meso-diaminopimelic acid and Mg2+ in Bacillus subtilis. Molecular Microbiology, 104(6), 972–988.
Résumé: The ability of excess Mg2+ to compensate the absence of cell wall related genes in Bacillus subtilis has been known for a long time, but the mechanism has remained obscure. Here, we show that the rigidity of wild-type cells remains unaffected with excess Mg2+, but the proportion of amidated meso-diaminopimelic (mDAP) acid in their peptidoglycan (PG) is significantly reduced. We identify the amidotransferase AsnB as responsible for mDAP amidation and show that the gene encoding it is essential without added Mg2+. Growth without excess Mg2+ causes asnB mutant cells to deform and ultimately lyse. In cell regions with deformations, PG insertion is orderly and indistinguishable from the wild-type. However, PG degradation is unevenly distributed along the sidewalls. Furthermore, asnB mutant cells exhibit increased sensitivity to antibiotics targeting the cell wall. These results suggest that absence of amidated mDAP causes a lethal deregulation of PG hydrolysis that can be inhibited by increased levels of Mg2+. Consistently, we find that Mg2+ inhibits autolysis of wild-type cells. We suggest that Mg2+ helps to maintain the balance between PG synthesis and hydrolysis in cell wall mutants where this balance is perturbed in favor of increased degradation.
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Feng, X. R., Ding, J. X., Gref, R., & Chen, X. S. (2017). Poly(beta-cyclodextrin)-mediated polylactide-cholesterol stereocomplex micelles for controlled drug delivery. Chinese Journal Of Polymer Science, 35(6), 693–699.
Résumé: A series of host-guest interaction-adjusted polylactide stereocomplex micelles was prepared via the self-assembly of 4-armed poly(ethylene glycol)-block-poly(L-lactide/D-lactide)-cholesterol (4-armed PEG-b-PLLA/PDLA-CHOL) and poly(beta-cyclodextrin) (PCD) with the molar ratios of CHOL/beta-CD at 1:0.5, 1:1, and 1:2 in an aqueous environment. The hydrodynamic diameters of the micelles ranged from 84.1 nm to 107 nm depending on the molar ratio of CHOL/beta-CD. It was shown that the micelle with the largest proportion of PCD possessed excellent abilities in drug release, cell internalization as well as proliferation inhibitory effect toward human A549 lung cancer cells. The results demonstrated that the stereocomplex and host-guest interactions-mediated PLA micelles exhibited great potential in sustained drug delivery.
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Gref, R., Couvreur, P., & Loftsson, T. (2017). Editorial Special edition of International Journal of Pharmaceutics in honor of Professor Dominique Duchene. International Journal Of Pharmaceutics, 531(2), 411–412.
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Hernandez, I. C., Sivankutty, S., Bourg, N., Lecart, S., Dupuis, G., & Leveque-Fort, S. (2017). A Novel STED Microscope with Nanometer Axial Sectioning. Biophysical Journal, 112(3), 140A–141A.
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Lacombe, S., Porcel, E., & Scifoni, E. (2017). Particle therapy and nanomedicine: state of art and research perspectives. Cancer nanotechnology, 8(1), 9.
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Li, H. Y., Lv, N. N., Li, X., Liu, B. T., Feng, J., Ren, X. H., Guo, T., Chen, D. W., Stoddart, J. F., Gref, R., & Zhang, J. W. (2017). Composite CD-MOF nanocrystals-containing microspheres for sustained drug delivery. Nanoscale, 9(22), 7454–7463.
Résumé: Metal-organic frameworks (MOFs), which are typically embedded in polymer matrices as composites, are emerging as a new class of carriers for sustained drug delivery. Most of the MOFs and the polymers used so far in these composites, however, are not pharmaceutically acceptable. In the investigation reported herein, composites of gamma-cyclodextrin (gamma-CD)-based MOFs (CD-MOFs) and polyacrylic acid (PAA) were prepared by a solid in oil-in-oil (s/o/o) emulsifying solvent evaporation method. A modified hydrothermal protocol has been established which produces efficiently at 50 degrees C in 6 h micron (5-10 μm) and nanometer (500-700 nm) diameter CD-MOF particles of uniform size with smooth surfaces and powder X-ray diffraction patterns that are identical with those reported in the literature. Ibuprofen (IBU) and Lansoprazole (LPZ), both insoluble in water and lacking in stability, were entrapped with high drug loading in nanometer-sized CD-MOFs by co-crystallisation (that is more effective than impregnation) without causing MOF crystal degradation during the loading process. On account of the good dispersion of drugloaded CD-MOF nanocrystals inside polyacrylic acid (PAA) matrices and the homogeneous distribution of the drug molecules within these crystals, the composite microspheres exhibit not only spherical shapes and sustained drug release over a prolonged period of time, but they also demonstrate reduced cell toxicity. The cumulative release rate for IBU (and LPZ) follows the trend: IBU-gamma-CD complex microspheres (ca. 80% in 2 h) > IBU microspheres > IBU-CD-MOF/PAA composite microspheres (ca. 50% in 24 h). Importantly, no burst release of IBU (and LPZ) was observed from the CD-MOF/PAA composite microspheres, suggesting an even distribution of the drug as well as strong drug carrier interactions inside the CD-MOF. In summary, these composite microspheres, composed of CD-MOF nanocrystals embedded in a biocompatible polymer (PAA) matrix, constitute an efficient and pharmaceutically acceptable MOFbased carrier for sustained drug release.
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Li, X., Guo, T., Lachmanski, L., Manoli, F., Menendez-Miranda, M., Manet, I., Guo, Z., Wu, L., Zhang, J. W., & Gref, R. (2017). Cyclodextrin-based metal-organic frameworks particles as efficient carriers for lansoprazole: Study of morphology and chemical composition of individual particles. International Journal Of Pharmaceutics, 531(2), 424–432.
Résumé: Cyclodextrin-based metal-organic frameworks (CD-MOFs) represent an environment-friendly and biocompatible class of MOFs drawing increasing attention in drug delivery. Lansoprazole (LPZ) is a proton-pump inhibitor used to reduce the production of acid in the stomach and recently identified as an antitubercular prodrug. Herein, LPZ loaded CD-MOFs were successfully synthesized upon the assembly with gamma-CD in the presence of K+ ions using an optimized co-crystallization method. They were characterized in terms of morphology, size and crystallinity, showing almost perfect cubic morphologies with monodispersed size distributions. The crystalline particles, loaded or not with LPZ, have mean diameters of around 6 μm. The payloads reached 23.2 +/- 2.1% (wt) which corresponds to a molar ratio of 1:1 between LPZ and gamma-CD. It was demonstrated that even after two years storage, the incorporated drug inside the CD-MOFs maintained its spectroscopic characteristics. Molecular modelling provided a deeper insight into the interaction between the LPZ and CD-MOFs. Raman spectra of individual particles were recorded, confirming the formation of inclusion complexes within the tridimensional CD-MOF structures. Of note, it was found that each individual particle had the same chemical composition. The LPZ-loaded particles had remarkable homogeneity in terms of both drug loading and size. These results pave the way towards the use of CD-MOFs for drug delivery purposes. (C) 2017 Elsevier B.V. All rights reserved.
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Li, X., Lachmanski, L., Safi, S., Sene, S., Serre, C., Greneche, J. M., Zhang, J., & Gref, R. (2017). New insights into the degradation mechanism of metal-organic frameworks drug carriers. Scientific Reports, 7, 13142.
Résumé: A versatile method based on Raman microscopy was developed to follow the degradation of iron carboxylate Metal Organic Framework (MOF) nano-or micro-particles in simulated body fluid (phosphate buffer). The analysis of both the morphology and chemical composition of individual particles, including observation at different regions on the same particle, evidenced the formation of a sharp erosion front during particle degradation. Interestingly, this front separated an intact non eroded crystalline core from an amorphous shell made of an inorganic network. According to Mossbauer spectrometry investigations, the shell consists essentially of iron phosphates. Noteworthy, neither drug loading nor surface modification affected the integrity of the tridimensional MOF network. These findings could be of interest in the further development of next generations of MOF drug carriers.
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Li, X., Salzano, G., Zhang, J. W., & Gref, R. (2017). Spontaneous Self-Assembly of Polymeric Nanoparticles in Aqueous Media: New Insights From Microfluidics, In Situ Size Measurements, and Individual Particle Tracking. Journal Of Pharmaceutical Sciences, 106(1), 395–401.
Résumé: Supramolecular cyclodextrin-based nanoparticles (CD-NPs) mediated by host-guest interactions have gained increased popularity because of their “green” and simple preparation procedure, as well as their versatility in terms of inclusion of active molecules. Herein, we showed that original CD-NPs of around 100 nm are spontaneously formed in water, by mixing 2 aqueous solutions of (1) a CD polymer and (2) dextran grafted with benzophenone moieties. For the first time, CD-NPs were instantaneously produced in a microfluidic interaction chamber by mixing 2 aqueous solutions of neutral polymers, in the absence of organic solvents. Whatever the mixing conditions, CD-NPs with narrow size distributions were immediately formed upon contact of the 2 polymeric solutions. In situ size measurements showed that the CD-NPs were spontaneously formed. Nanoparticle tracking analysis was used to individually follow the CD-NPs in their Brownian motions, to gain insights on their size distribution, concentration, and stability on extreme dilution. Nanoparticle tracking analysis allowed to establish that despite their non-covalent nature, and the CD-NPs were remarkably stable in terms of concentration and size distribution, even on extreme dilution (concentrations as low as 100 ng/mL). (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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Lv, N. N., Guo, T., Liu, B. T., Wang, C. F., Singh, V., Xu, X. N., Li, X., Chen, D. W., Gref, R., & Zhang, J. W. (2017). Improvement in Thermal Stability of Sucralose by Y-Cyclodextrin Metal-Organic Frameworks. Pharmaceutical Research, 34(2), 269–278.
Résumé: Purpose To explain thermal stability enhancement of an organic compound, sucralose, with cyclodextrin based metal organic frameworks. Methods Micron and nanometer sized basic CD-MOFs were successfully synthesized by a modified vapor diffusion method and further neutralized with glacial acetic acid. Sucralose was loaded into CD-MOFs by incubating CDMOFs with sucralose ethanol solutions. Thermal stabilities of sucralose-loaded basic CD-MOFs and neutralized CDMOFs were investigated using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography with evaporative lightscattering detection (HPLC-ELSD). Results Scanning electron microscopy (SEM) and powder Xray diffraction (PXRD) results showed that basic CD-MOFs were cubic crystals with smooth surface and uniform sizes. The basic CD-MOFs maintained their crystalline structure after neutralization. HPLC-ELSD analysis indicated that the CD-MOF crystal size had significant influence on sucralose loading (SL). The maximal SL of micron CD-MOFs (CDMOF-Micro) was 17.5 +/- 0.9% (w/w). In contrast, 27.9 +/- 1.4% of sucralose could be loaded in nanometer-sized basic CD-MOFs (CD-MOF-Nano). Molecular docking modeling showed that sucralose molecules preferentially located inside the cavities of gamma-CDs pairs in CD-MOFs. Raw sucralose decomposed fast at 90(o)C, with 86.2 +/- 0.2% of the compound degraded within only 1 h. Remarkably, sucralose stability was dramatically improved after loading in neutralized CDMOFs, with only 13.7 +/- 0.7% degradation at 90(o)C within 24 h. Conclusions CD-MOFs efficiently incorporated sucralose and maintained its integrity upon heating at elevated temperatures.
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Marcos-Almaraz, M. T., Gref, R., Agostoni, V., Kreuz, C., Clayette, P., Serre, C., Couvreur, P., & Horcajada, P. (2017). Towards improved HIV-microbicide activity through the co-encapsulation of NRTI drugs in biocompatible metal organic framework nanocarriers. Journal Of Materials Chemistry B, 5(43), 8563–8569.
Résumé: The efficacy of the routinely used anti-HIV (Human Immunodeficiency Virus) therapy based on nucleoside reverse transcriptase inhibitors (NRTIs) is limited by the poor cellular uptake of the active triphosphorylated metabolites and the low efficiency of intracellular phosphorylation of their prodrugs. Nanoparticles of iron(III) polycarboxylate Metal-Organic Frameworks (nanoMOFs) are promising drug nanocarriers. In this study, two active triphosphorylated NRTIs, azidothymidine triphosphate (AZT-Tp) and lamivudine triphosphate (3TC-Tp), were successfully co-encapsulated into the biocompatible mesoporous iron(III) trimesate MIL-100(Fe) nanoMOF in order to improve anti-HIV therapies. The drug loaded nanoMOFs could be stored for up to 2-months and reconstituted after freeze drying, retaining similar physicochemical properties. Their antiretroviral activity was evidenced in vitro on monocyte-derived macrophages experimentally infected with HIV, making these co-encapsulated nanosystems excellent HIV-microbicide candidates.
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Marechal, D., Daudin, R., Bourg, N., Loe-Mie, Y., Potier, B., Dutar, P., Viard, J., Lepagnol-Bestel, A., Sartori, M., Hindie, V., Birling, M., Pavlovic, G., Dupuis, G., Fort, S. L., Laporte, J., Rain, J., Simonneau, M., & Herault, Y. (2017). Risk factor gene BIN1 induces late onset Alzheimer disease presymptomatic phenotypes in a BAC transgenic mouse model. European Neuropsychopharmacology, 27, S742–S743.
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Nouman, M., Saunier, J., Jubeli, E., Marliere, C., & Yagoubi, N. (2017). Impact of of sterilization and oxidation processes on the additive blooming observed on the surface of polyurethane. European Polymer Journal, 90, 37–53.
Résumé: The surface state is a major parameter for the biocompatibility of medical devices. During storage, the blooming of additives may occur on the surface of polymers and modify their properties. In this study, the impact of sterilizing and oxidation treatments on blooming was studied. The study was realized on polyurethane used in the fabrication of catheters on which the blooming of antioxidant crystals has been previously observed. Sterilization by ionizing radiations (beta, gamma) was performed on this material and samples were submitted to different kinds of oxidation process (UV, H2O2 and macrophages action). Surface evolution was investigated using AFM microscopy, FTIR-ATR and SEM.
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Ortega, J. M., Glotin, F., Prazeres, R., Li, X., & Gref, R. (2017). Far infrared micro-spectroscopy: an innovative method to detect individual metal-organic framework particles. Applied Optics, 56(23), 6663–6667.
Résumé: The purpose of this study is to extend the spectral range of a differential method of infrared micro-spectroscopy in order to allow the accurate detection of nanoparticles of interest for biomedical applications. Among these, metal-organic framework (MOF) nanoparticles have attracted increasing interest due to their capacity to incorporate high drug payloads, biodegradability, and possibility of tailoring their surfaces by grafting specific ligands. However, MOF particle detection in biological media without grafting or incorporating fluorescent molecules is challenging. We took advantage here of the presence of the specific absorption bands of nanoscale MOFs in far infrared in order to individually discriminate them. Here we show that single MOF nanoparticles can be imaged with a spatial resolution of a few tens of nanometers. (C) 2017 Optical Society of America
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Rodriguez-Ruiz, V., Maksimenko, A., Salzano, G., Lampropoulou, M., Lazarou, Y. G., Agostoni, V., Couvreur, P., Gref, R., & Yannakopoulou, K. (2017). Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells. Scientific Reports, 7, 8353.
Résumé: Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino-and aminoalkyl-PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active molecules bearing phosphate groups. We have addressed here the challenge to deliver into cancer cells phosphorylated gemcitabine drugs well known for their instability and inability to permeate cell membranes. NMR data corroborated by semiempirical theoretical calculations have shown that aminoalkyl-CDs form sufficiently stable complexes with both mono-and tri-phosphate forms of gemcitabine by simple mixing of the compounds in aqueous solution at physiological pH. Confocal microscopy and radioactivity counting experiments revealed that the developed systems enabled phosphorylated gemcitabine to penetrate efficiently into aggressive human breast cancer cells (MCF7), eventually leading to a substantial reduction of IC50 values. Moreover, compared to free drugs, phosphorylated metabolites of gemcitabine encapsulated in PCCDs displayed improved in vitro activities also on the aggressive human cancer cells CCRF-CEM Ara-C/8 C, a nucleoside transport-deficient T leukemia cell line. The current study offers the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cancer cells.
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Salzano, G., Wankar, J., Ottani, S., Villemagne, B., Baulard, A. R., Willand, N., Brodin, P., Manet, I., & Gref, R. (2017). Cyclodextrin-based nanocarriers containing a synergic drug combination: A potential formulation for pulmonary administration of antitubercular drugs. International Journal Of Pharmaceutics, 531(2), 577–587.
Résumé: Tuberculosis (TB) remains a major global health problem. The use of ethionamide (ETH), a main second line drug, is associated to severe toxic side-effects due to its low therapeutic index. In this challenging context, “booster” molecules have been synthetized to increase the efficacy of ETH. However, the administration of ETH/booster pair is mostly hampered by the low solubility of these drugs and the tendency of ETH to crystallize. Here, ETH and a poorly water-soluble booster, so-called BDM43266, were simultaneously loaded in polymeric beta-cyclodextrin nanoparticles (p beta CyD NPs) following a “green” protocol. The interaction of ETH and BDM43266 with p beta CyD NPs was investigated by complementary techniques. Remarkably, the inclusion of ETH and BDM43266 pbCyD NPs led to an increase of their apparent solubility in water of 10-and 90-fold, respectively. Competition studies of ETH and BDM43266 for the CyD cavities of p beta CyD NPs corroborated the fact that the drugs did not compete with each other, confirming the possibility to simultaneously co-incorporate them in NPs. The drug-loaded NP suspensions could be filtered through 0.22 μm filters. Finally, the drug-loaded NPs were passed through a Microsprayer (R) to evaluate the feasibility to administer p beta CyD NPs by pulmonary route. Each spray delivered a constant amount of both drugs and the NPs were totally recovered after passage through the Microsprayer (R). These promising results pave the way for a future use of p beta CyD NPs for the pulmonary delivery of the ETH/BDM43266 pair. (C) 2017 Published by Elsevier B.V.
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Sarsa, A., Alcaraz-Pelegrina, J. M., & Le Sech, C. (2017). The hydrogen atom confined by one and two hard cones. Physics Letters A, 381(8), 780–786.
Résumé: The bound states of the H atom in a semi-infinite space limited by one or two conical boundaries are studied. The exact solution when the nucleus is located at the apex of the conical boundaries is obtained. A rapid increase of the energy when the cone angle opens and tends to pi/2 is found. A second situation with the atom separated from the summit of the cone is considered. The changes on the energy and the electronic structure are analyzed. The quantum force is evaluated by calculating the energy derivative versus the distance to the cone vertex. One of the forces exerted on the tip of an Atomic Force Microscope can be modelized by a hard cone probing the electron cloud in the contact mode. Our numerical results show that the quantum force present an important dependence with the cone angle and it vanishes rapidly as the distance increases. (C) 2016 Elsevier B.V. All rights reserved.
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Saunier, J., Herry, J. M., Yagoubi, N., & Marliere, C. (2017). Exploring complex transitions between polymorphs on a small scale by coupling AFM, FTIR and DSC: the case of Irganox 1076 (R) antioxidant. Rsc Advances, 7(7), 3804–3818.
Résumé: This study illustrates the significant interest of using atomic force microscopy (AFM) in force curve imaging mode for discovering and studying not easily detectable solid/solid transitions between polymorphs: we show that AFM in this imaging mode is a powerful means for studying in situ these transitions as they can be (i) detected in a very early step because of the high spatial resolution (at nanometer scale) of AFM and (ii) be distinguished from melting/recrystallization processes that can occur in the same temperature range. This was illustrated with the case of Irganox 1076 (R). This compound is a phenolic antioxidant currently used in standard polymers; it can bloom on the surface of polymer-based medical devices and its polymorphism might affect the device surface state and thus the biocompatibility. In a previous paper, the polymorphism of this compound was studied: four forms were characterized at a macroscopic level and one of them (form III) was identified on the surface of a polyurethane catheter. However, it was difficult to characterize the transitions between the different forms with only classical tools (DSC, FTIR and SAXS). In the present study, to evidence these transitions, we use AFM measurements coupled with a heating stage and we correlate them to ATR-FTIR measurements and to DSC analysis. This new study put into evidence a solid-solid transition between form III and II.
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Simon-Yarza, T., Gimenez-Marques, M., Mrimi, R., Mielcarek, A., Gref, R., Horcajada, P., Serre, C., & Couvreur, P. (2017). A Smart Metal-Organic Framework Nanomaterial for Lung Targeting. Angewandte Chemie-International Edition, 56(49), 15565–15569.
Résumé: Despite high morbidity and mortality associated with lung diseases, addressing drugs towards lung tissue remains a pending task. Particle lung filtration has been proposed for passive lung targeting and drug delivery. However, toxicity issues derived from the long-term presence of the particles must be overcome. By exploiting some of the ignored properties of nanosized metal-organic frameworks it is possible to achieve impressive antitumoral effects on experimental lung tumors, even without the need to engineer the surface of the material. In fact, it was discovered that, based on unique pH-responsiveness and reversible aggregation behaviors, nanoMOF was capable of targeting lung tissue. At the neutral pH of the blood, the nanoMOFs form aggregates with the adequate size to be retained in lung capillaries. Within 24 h they then disaggregate and release their drug payload. This phenomenon was compatible with lung tissue physiology.
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Singh, V., Guo, T., Wu, L., Xu, J. H., Liu, B. T., Gref, R., & Zhang, J. W. (2017). Template-directed synthesis of a cubic cyclodextrin polymer with aligned channels and enhanced drug payload. Rsc Advances, 7(34), 20789–20794.
Résumé: Despite its 3D porous structure, the pharmaceutical applications of cyclodextrin based cross-linked polymers are limited due to their structural irregularities. To address this issue, a template-directed strategy is used to obtain cubic micro and nano cyclodextrin cross-linked polymer (CD-cubes) from cyclodextrin metal organic frameworks in this study. The well-organized gamma-CDs in MOFs were crosslinked by diphenyl carbonate by a facile single step chemical reaction. Scanning electron microscopy and X-ray diffraction analysis revealed the almost perfect cubic shapes of the particles with a disordered internal structure. Contrarily to the non-crosslinked materials which immediately dissolved in water, the CD-cubes were remarkably stable after extensive washing with water. The CD-cubes possessed a mesoporous structure with pore size in the range of 2-4 nm and showed much higher BET surface and 8 times higher adsorption capacity for doxorubicin as compared to conventional cyclodextrin-sponges.
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Singh, V., Guo, T., Xu, H. T., Wu, L., Gu, J. K., Wu, C. B., Gref, R., & Zhang, J. W. (2017). Moisture resistant and biofriendly CD-MOF nanoparticles obtained via cholesterol shielding. Chemical Communications, 53(66), 9246–9249.
Résumé: A facile and one step-method was developed to enhance the water stability of CD-MOF nanoparticles through surface modification with cholesterol. CD-MOFs were able to maintain their cubic crystalline structures even after 24 h of incubation, well tolerated in vivo and could increase up to 4 times the blood half-life of DOX.
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Singh, V., Xu, J. H., Wu, L., Liu, B. T., Guo, T., Guo, Z., York, P., Gref, R., & Zhang, J. W. (2017). Ordered and disordered cyclodextrin nanosponges with diverse physicochemical properties. Rsc Advances, 7(38), 23759–23764.
Résumé: Herein, in addition to conventional beta-CD-NSPs, the NSPs of alpha, gamma, HP-beta, methyl-beta, and SBE-beta cyclodextrins were synthesized by a simple modified approach and thoroughly characterized. The control of CDs derivatization over structural dimensions and properties was clearly observed. It is interesting to note the complete transformation of beta-CD from its crystalline form to its non-crystalline derivatives and the further reversal when the derivatives are prepared into NSPs including those of a and gamma-CDs (as observed by PXRD). The SEM images revealed the different morphologies and porous structure of NSPs and, in particular, the NSPs of methyl-beta-CD exhibited regular spherical shapes. Two drugs of different categories, doxorubicin and captopril, were evaluated for loading efficiencies, which were found to significantly vary with cross-linker ratio (1 : 4 and 1 : 6) and CD types. Together, all the synthesized NSPs provide a new horizon to try to solve existing problems relating to drug delivery.
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Wankar, J., Salzano, G., Pancani, E., Benkovics, G., Malanga, M., Manoli, F., Gref, R., Fenyvesi, E., & Manet, I. (2017). Efficient loading of ethionamide in cyclodextrin-based carriers offers enhanced solubility and inhibition of drug crystallization. International Journal Of Pharmaceutics, 531(2), 568–576.
Résumé: Ethionamide (ETH) is a second line antitubercular drug suffering from poor solubility in water and strong tendency to crystallize. These drawbacks were addressed by loading ETH in beta-cyclodextrin (beta CyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25 mM. The binding of ETH to polymeric beta CyD nanoparticles (p beta CyD NPs) was investigated in neutral aqueous medium by means of solubility phase diagrams, circular dichroism (CD) and UV-vis absorption and compared with the corresponding beta CyD monomer. The binding constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ETH included in the cavity. Additionally, ETH was found to be located not only in beta CyD cavities, but also in confined microdomains inside the crosslinked NPs. This double modality of complexation together with a slightly higher binding constant makes the utilization of p beta CyD NPs preferable over the monomeric beta CyDs. In order to pave the way to future in vitro experiments, fluorescein labeled p beta CyDs were synthesized. Interestingly the FITC labeling did not hamper the encapsulation of ETH and the drug improved the fluorescent signal of FITC molecules. The beta CyD-based carriers appeared as versatile “green” systems for efficient incorporation and future delivery of ETH. (C) 2017 Elsevier B.V. All rights reserved.
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Xu, X. N., Wang, C. F., Li, H. Y., Li, X., Liu, B. T., Singh, V. J., Wang, S. X., Sun, L. X., Gref, R. X., & Zhang, J. W. (2017). Evaluation of drug loading capabilities of gamma-cyclodextrin-metal organic frameworks by high performance liquid chromatography. Journal Of Chromatography A, 1488, 37–44.
Résumé: Drug loading into gamma-cyclodextrin-metal organic frameworks (gamma-CD-MOFs) using the impregnation approach is a laborious process. In this study, a gamma-CD-MOF construct (2-5 μm particle diameter) was used as the stationary phase under HPLC conditions with the aim to correlate retention properties and drug loading capability of the CD-based structure. Ketoprofen, fenbufen and diazepam were chosen as model drugs with m-xylene as a control analyte to investigate the correlation of drug loading and their chromatographic behaviour in the gamma-CD-MOF column. Furthermore, gamma-CD itself was also prepared as the stationary phase by coupling with silica in the column to illustrate the enhanced interaction between drugs and gamma-CD-MOF as a reference. The retention and loading efficiency of the drugs were determined with different ratios of hexane and ethanol (10:90, 20:80, 50:50, 80:20, 90:10, v/v) at temperatures of 20, 25, 30 and 37 degrees C. With the increment in hexane content, the loading efficiency of ketoprofen and fenbufen increased from 2.39 +/- 0.06% to 4.38 +/- 0.04% and from 5.82 +/- 0.94% to 6.37 +/- 0.29%, respectively. The retention time and loading efficiency of ketoprofen and diazepam were the lowest at 30 degrees C while those of fenbufen had the different tendency. The excellent relation between the retention and loading efficiency onto gamma-CD-MOF could be clearly observed through mobile phase and temperature investigation. In conclusion, a highly efficient chromatographic method has been established to evaluate the drug loading capability of gamma-CD-MOF. (C) 2017 Elsevier B.V. All rights reserved
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Actes de Conférences |
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Falk, M., Stefancikova, L., Lacombe, S., Salado, D., Porcel, E., Pagacova, E., Tillement, O., Lux, F., Depes, D., Falkova, I., Bacikova, A., & Kozubek, S. (2017). Radiosensitization of resistant (Head and Neck) tumor cells by metal nanoparticles. In Febs Journal (Vol. 284, p. 255).
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