Peer-reviewed Publications |
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Chaupard, M., de Frutos, M., & Gref, R. (2021). Deciphering the Structure and Chemical Composition of Drug Nanocarriers: From Bulk Approaches to Individual Nanoparticle Characterization. Part. Part. Syst. Charact., .
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Christodoulou I, B. T., Li X, Patriarche G, Serre C, Marlière C, Gref R. (2021). Degradation Mechanism of Porous Metal-Organic Frameworks by In Situ Atomic Force Microscopy. Nanomaterials (Basel), 11(3), 722.
Résumé: In recent years, Metal-Organic Frameworks (MOFs) have attracted a growing interest for biomedical applications. The design of MOFs should take into consideration the subtle balance between stability and biodegradability. However, only few studies have focused on the MOFs' stability in physiological media and their degradation mechanism. Here, we investigate the degradation of mesoporous iron (III) carboxylate MOFs, which are among the most employed MOFs for drug delivery, by a set of complementary methods. In situ AFM allowed monitoring with nanoscale resolution the morphological, dimensional, and mechanical properties of a series of MOFs in phosphate buffer saline and in real time. Depending on the synthetic route, the external surface presented either well-defined crystalline planes or initial defects, which influenced the degradation mechanism of the particles. Moreover, MOF stability was investigated under different pH conditions, from acidic to neutral. Interestingly, despite pronounced erosion, especially at neutral pH, the dimensions of the crystals were unchanged. It was revealed that the external surfaces of MOF crystals rapidly respond to in situ changes of the composition of the media they are in contact with. These observations are of a crucial importance for the design of nanosized MOFs for drug delivery applications.
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Jouchet, P., Cabriel, C., Bourg, N., Bardou, M., Poüs, C., Fort, E., & Lévêque-Fort, S. (2021). Nanometric axial localization of single fluorescent molecules with modulated excitation. Nat. Photonics, 15, 297.
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Li, X., Porcino, M., Qiu, J., Constantin, D., Martineau-Corcos, C., & Gref, R. (2021). Doxorubicin-Loaded Metal-Organic Frameworks Nanoparticles with Engineered Cyclodextrin Coatings: Insights on Drug Location by Solid State NMR Spectroscopy. Nanomaterials (Basel), 11(4), 945.
Résumé: Recently developed, nanoscale metal-organic frameworks (nanoMOFs) functionalized with versatile coatings are drawing special attention in the nanomedicine field. Here we show the preparation of core-shell MIL-100(Al) nanoMOFs for the delivery of the anticancer drug doxorubicin (DOX). DOX was efficiently incorporated in the MOFs and was released in a progressive manner, depending on the initial loading. Besides, the coatings were made of biodegradable gamma-cyclodextrin-citrate oligomers (CD-CO) with affinity for both DOX and the MOF cores. DOX was incorporated and released faster due to its affinity for the coating material. A set of complementary solid state nuclear magnetic resonance (ssNMR) experiments including (1)H-(1)H and (13)C-(27)Al two-dimensional NMR, was used to gain a deep understanding on the multiple interactions involved in the MIL-100(Al) core-shell system. To do so, (13)C-labelled shells were synthesized. This study paves the way towards a methodology to assess the nanoMOF component localization at a molecular scale and to investigate the nanoMOF physicochemical properties, which play a main role on their biological applications.
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Mau, A., Friedl, K., Leterrier, C., Bourg N, & Leveque-Fort, S. (2021). Fast widefield scan provides tunable and uniform illumination optimizing super-resolution microscopy on large fields. Nat Commun, 12, 3077.
Résumé: Non-uniform illumination limits quantitative analyses of fluorescence imaging techniques. In particular, single molecule localization microscopy (SMLM) relies on high irradiances, but conventional Gaussian-shaped laser illumination restricts the usable field of view to around 40 microm x 40 microm. We present Adaptable Scanning for Tunable Excitation Regions (ASTER), a versatile illumination technique that generates uniform and adaptable illumination. ASTER is also highly compatible with optical sectioning techniques such as total internal reflection fluorescence (TIRF). For SMLM, ASTER delivers homogeneous blinking kinetics at reasonable laser power over fields-of-view up to 200 microm x 200 microm. We demonstrate that ASTER improves clustering analysis and nanoscopic size measurements by imaging nanorulers, microtubules and clathrin-coated pits in COS-7 cells, and beta2-spectrin in neurons. ASTER's sharp and quantitative illumination paves the way for high-throughput quantification of biological structures and processes in classical and super-resolution fluorescence microscopies.
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Porcino, M., Li, X., Gref, R., & Martineau-Corcos C. (2021). Solid-state NMR spectroscopy as a powerful tool to investigate the location of fluorinated lipids in highly porous hybrid organic-inorganic nanoparticles. Magn Reson Chem, .
Résumé: Nanosized metal-organic frameworks (nanoMOFs) have emerged as a new class of biodegradable and nontoxic nanomaterials of high interest for biomedical applications thanks to the possibility to load large amounts of a wide variety of therapeutic molecules in their porous structure. The surface of the highly porous nanoMOFs is usually engineered to increase their colloidal stability, to tune their interactions with the biological environment, and to allow targeting specific cells or organs. However, the atomic-scale analysis of these complex core-shell materials is highly challenging. In this study, we report the investigation of aluminum-based nanoMOFs containing two fluorinated lipids by solid-state NMR spectroscopy, including (27) Al, (1) H and (19) F MAS NMR. The ensemble of NMR data provides a better understanding of the localization and conformation of the fluorinated lipids inside the pores or on the nanoMOF surface.
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Orre T, Joly A, Karatas, Z., Kastberger, B., Cabriel, C., Bottcher RT, Leveque-Fort S, Sibarita, J. - B., Fassler R, Wehrle-Haller B, Rossier, O., & Giannone G. (2021). Molecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions. (Vol. 12).
Résumé: Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. Using single protein tracking, super-resolution microscopy and functional assays, we link the molecular behavior and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs. We show that immobilization of integrins in FAs depends on interaction with kindlin. Unlike talin, kindlin displays free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation, cell spreading and FAs formation. Thus, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation.
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Porcino M, Li, X., Gref R, & Martineau-Corcos C. (2021). Solid-State NMR Spectroscopy: A Key Tool to Unravel the Supramolecular Structure of Drug Delivery Systems..
Résumé: In the past decades, nanosized drug delivery systems (DDS) have been extensively developed and studied as a promising way to improve the performance of a drug and reduce its undesirable side effects. DDSs are usually very complex supramolecular assemblies made of a core that contains the active substance(s) and ensures a controlled release, which is surrounded by a corona that stabilizes the particles and ensures the delivery to the targeted cells. To optimize the design of engineered DDSs, it is essential to gain a comprehensive understanding of these core-shell assemblies at the atomic level. In this review, we illustrate how solid-state nuclear magnetic resonance (ssNMR) spectroscopy has become an essential tool in DDS design.
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Siyu He, L. W., Xue Li, Hongyu Sun, Ting Xiong, Jie Liu, Chengxi Huang, Huipeng Xu, Huimin Sun, Weidong Chen, Ruxandra Gref, Jiwen Zhang. (2021). Metal-organic frameworks for advanced drug delivery..
Résumé: Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters via coordinative bonds are highly porous, crystalline materials. Their tunable porosity, chemical composition, size and shape, and easy surface functionalization make this large family more and more popular for drug delivery. There is a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications. This article presents an overall review and perspectives of MOFs-based drug delivery systems (DDSs), starting with the MOFs classification adapted for DDSs based on the types of constituting metals and ligands. Then, the synthesis and characterization of MOFs for DDSs are developed, followed by the drug loading strategies, applications, biopharmaceutics and quality control. Importantly, a variety of representative applications of MOFs are detailed from a point of view of applications in pharmaceutics, diseases therapy and advanced DDSs. In particular, the biopharmaceutics and quality control of MOFs-based DDSs are summarized with critical issues to be addressed. Finally, challenges in MOFs development for DDSs are discussed, such as biostability, biosafety, biopharmaceutics and nomenclature.
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