Peer-reviewed Publications |
Kena Zhao, T. G., Caifen Wang, Yong Zhou, Ting Xiong, Li Wu, Xue Li, Priyanka Mittal, Senlin Shi, Ruxandra Gref. (2020). Glycoside scutellarin enhanced CD-MOF anchoring for laryngeal delivery. Acta Pharm Sin B, 10(9), 1709.
Résumé: It is essential to develop new carriers for laryngeal drug delivery in light of the lack of therapy in laryngeal related diseases. When the inhalable micron-sized crystals of gamma-cyclodextrin metal-organic framework (CD-MOF) was utilized as dry powder inhalers (DPIs) carrier with high fine particle fraction (FPF), it was found in this research that the encapsulation of a glycoside compound, namely, scutellarin (SCU) in CD-MOF could significantly enhance its laryngeal deposition. Firstly, SCU loading into CD-MOF was optimized by incubation. Then, a series of characterizations were carried out to elucidate the mechanisms of drug loading. Finally, the laryngeal deposition rate of CD-MOF was 57.72 +/- 2.19% improved by SCU, about two times higher than that of CD-MOF, when it was determined by Next Generation Impactor (NGI) at 65 L/min. As a proof of concept, pharyngolaryngitis therapeutic agent dexamethasone (DEX) had improved laryngeal deposition after being co-encapsulated with SCU in CD-MOF. The molecular simulation demonstrated the configuration of SCU in CD-MOF and its contribution to the free energy of the SCU@CD-MOF, which defined the enhanced laryngeal anchoring. In conclusion, the glycosides-like SCU could effectively enhance the anchoring of CD-MOF particles to the larynx to facilitate the treatment of laryngeal diseases.
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Le Sech, C., Le Sech C, Hirayama, R., & Hirayama R. (2020). Dual aspect of radioenhancers and free radical scavengers. Free Radic Biol Med, .
Résumé: Combining an external beam of ionizing particles with agents to augment the dose effects of cell damages for therapeutic purpose is an important goal of radiotherapy. This last decade intensive works have focused on metal compounds or metal nanoparticles as radiosensitizers to increase the oxidative damages under irradiation. In principle the nanoparticles can be coated with a functionalized shell, to achieve a specific targeting of the tissues, making such approach attractive. The functionalized coating is made of polymers. These molecules are able to scavenge the free radicals, thus, the coating can decrease the overall efficacy of the radiation. The purpose of the present model is to analyse the role of free hydroxyl radicals in the dual behaviour of the added agent. Consideration of the efficiency of the added agents versus the Linear Energy Transfer – LET – of the ionizing particles is made. It is shown that an efficient agent combined with a low-LET particle beams might become less efficient when high-LET particles like heavy-ions are used. These general considerations should be useful to optimize the design of the nanoparticles to be combined with the different kind of ionizing particles.
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Li, X., Porcino, M., Martineau-Corcos, C., Guo, T., Xiong, T., Zhu, W. F., Patriarche, G., Pechoux, C., Perronne, B., Hassan, A., Kummerle, R., Michelet, A., Zehnacker-Rentien, A., Zhang, J. W., & Gref, R. (2020). Efficient incorporation and protection of lansoprazole in cyclodextrin metal-organic frameworks. International Journal of Pharmaceutics, 585, 119442.
Résumé: Lansoprazole (LPZ) is an acid pump inhibitor, which readily degrades upon acidic or basic conditions and under heating. We investigated here LPZ stability upon incorporation in particles made of cyclodextrin metal-organic frameworks (CD-MOFs). LPZ loaded CD-MOFs were successfully synthesized, reaching high LPZ payloads of 23.2 +/- 2.1 wt%, which correspond to a molar ratio of 1:1 between LPZ and gamma-CD. The homogeneity of LPZ loaded CD-MOFs in terms of component distribution was confirmed by elemental mapping by STEM-EDX. Both CTAB, the surfactant used in the CD-MOFs synthesis, and LPZ compete for their inclusion in the CD cavities. CTAB allowed obtaining regular cubic particles of around 5 μm with 15 wt% residual CTAB amounts. When LPZ was incorporated, the residual CTAB amount was less than 0.1 wt%, suggesting a higher affinity of LPZ for the CDs than CTAB. These findings were confirmed by molecular simulations. Vibrational circular dichroism studies confirmed the LPZ incorporation inside the CDs. Solid-state NMR showed that LPZ was located in the CDs and that it remained intact even after three years storage. Remarkably, the CD-MOFs matrix protected the drug upon thermal decomposition. This study highlights the interest of CD-MOFs for the incorporation and protection of LPZ.
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Li, X., Salzano, G., Qiu, J., Menard, M., Berg, K., Theodossiou, T., Ladaviere, C., & Gref, R. (2020). Drug-Loaded Lipid-Coated Hybrid Organic-Inorganic “Stealth” Nanoparticles for Cancer Therapy. Front Bioeng Biotechnol, .
Résumé: Hybrid porous nanoscale metal organic frameworks (nanoMOFs) made of iron trimesate are attracting increasing interest as drug carriers, due to their high drug loading capacity, biodegradability, and biocompatibility. NanoMOF surface modification to prevent clearance by the innate immune system remains still challenging in reason of their high porosity and biodegradable character. Herein, FDA-approved lipids and poly(ethylene glycol) (PEG)-lipid conjugates were used to engineer the surface of nanoMOFs by a rapid and convenient solvent-exchange deposition method. The resulting lipid-coated nanoMOFs were extensively characterized. For the first time, we show that nanoMOF surface modification with lipids affords a better control over drug release and their degradation in biological media. Moreover, when loaded with the anticancer drug Gem-MP (Gemcitabine-monophosphate), iron trimesate nanoMOFs acted as “Trojan horses” carrying the drug inside cancer cells to eradicate them. Most interestingly, the PEG-coated nanoMOFs escaped the capture by macrophages. In a nutshell, versatile PEG-based lipid shells control cell interactions and open perspectives for drug targeting.
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Siddharth Sivankutty, I. C. H., Nicolas Bourg, Guillaume Dupuis, Sandrine Lévêque-Fort. (2020). Supercritical angle fluorescence for enhanced axial sectioning in STED microscopy. Methods, 174, 20–26.
Résumé: We demonstrate subwavelength axial sectioning on biological samples with a stimulated emission depletion (STED) microscope combined with supercritical angle fluorescence (SAF) detection. SAF imaging is a powerful technique for imaging the membrane of the cell based on the direct exploitation of the fluorophore emission properties. Indeed, only when fluorophores are close to the interface can their evanescent near-field emission become propagative and be detected beyond the critical angle. Therefore, filtering out the SAF emission from the undercritical angle fluorescence (UAF) emission in the back focal plane of a high-NA objective lens permits nanometer axial sectioning of fluorescent emitters close to the coverslip. When combined with STED microscopy, a straightforward gain in axial resolution can be reached without any alteration of the STED beam path. Indeed, STED-SAF implementation only requires a modification in the detection path of the STED microscope and thus could be widely implemented.
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Chapitres de Livres |
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I Christodoulou, C. S., R Gref. (2020). Metal-organic frameworks for drug delivery: Degradation mechanism and in vivo fate. In Metal-Organic Frameworks for Biomedical Applications (pp. 467–489).
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Gref, R., Delomenie C, Maksimenko A, Gouadon E, Percoco, G., Lati E, Desmaele, D., Zouhiri, F., & Couvreur P. (2020). Vitamin C-squalene bioconjugate promotes epidermal thickening and collagen production in human skin. (Vol. 10).
Résumé: Vitamin C (Vit C) benefits to human skin physiology notably by stimulating the biosynthesis of collagen. The main cutaneous collagens are types I and III, which are less synthesized with aging. Vit C is one of the main promotors of collagen formation but it poorly bypasses the epidermis stratum corneum barrier. To address this challenge, we developed a lipophilic version of Vit C for improving skin diffusion and delivery. Vit C was covalently conjugated to squalene (SQ), a natural lipid of the skin, forming a novel Vit C-SQ derivative suitable for cream formulation. Its biological activity was investigated on human whole skin explants in an ex vivo model, through histology and protein and gene expression analyses. Results were compared to Vit C coupled to the reference lipophilic compound palmitic acid, (Vit C-Palmitate). It was observed that Vit C-SQ significantly increased epidermal thickness and preferentially favored collagen III production in human skin after application for 10 days. It also promoted glycosaminoglycans production in a higher extent comparatively to Vit C-Palmitate and free Vit C. Microdissection of the explants to separate dermis and epidermis allowed to measure higher transcriptional effects either in epidermis or in dermis. Among the formulations studied, the strongest effects were observed with Vit C-SQ.
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Li X, Porcel, E., Menendez-Miranda, M., Qiu, J., Yang, X., Serre, C., Pastor, A., Desmaele, D., Lacombe S, & Gref, R. (2020). Highly Porous Hybrid Metal-Organic Nanoparticles Loaded with Gemcitabine Monophosphate: a Multimodal Approach to Improve Chemo- and Radiotherapy. (Vol. 15).
Résumé: Nanomedicine recently emerged as a novel strategy to improve the performance of radiotherapy. Herein we report the first application of radioenhancers made of nanoscale metal-organic frameworks (nanoMOFs), loaded with gemcitabine monophosphate (Gem-MP), a radiosensitizing anticancer drug. Iron trimesate nanoMOFs possess a regular porous structure with oxocentered Fe trimers separated by around 5 A (trimesate linkers). This porosity is favorable to diffuse the electrons emitted from nanoMOFs due to activation by gamma radiation, leading to water radiolysis and generation of hydroxyl radicals which create nanoscale damages in cancer cells. Moreover, nanoMOFs act as “Trojan horses”, carrying their Gem-MP cargo inside cancer cells to interfere with DNA repair. By displaying different mechanisms of action, both nanoMOFs and incorporated Gem-MP contribute to improve radiation efficacy. The radiation enhancement factor of Gem-MP loaded nanoMOFs reaches 1.8, one of the highest values ever reported. These results pave the way toward the design of engineered nanoparticles in which each component plays a role in cancer treatment by radiotherapy.
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Usami, N., Usami N, Hirayama, R., Hirayama R, Kobayashi, K., Kobayashi K, Furusawa, Y., Furusawa Y, Le Sech, C., & Le Sech C. (2020). Combination of agents modifying effects in hadrontherapy: modelization of the role of HO degrees free radicals..
Résumé: Purpose: A study is presented of the irradiation of cancerous cervical cell line HeLa loaded with a platinum salt, betamethasone and deoxyglucose. The presence of the platinum increases the free-radical concentration and augments the cell death rate, whereas betamethasone or deoxyglucose induces radiosensitization by the alteration of metabolic pathways. Two by two combinations of these chemicals are made to investigate the possible benefit when two radiosensitizers are present. A model is proposed to understand the results of the presence of two modifying agents on the dose effects.Materials and methods: The cells were incubated for 6 h in the presence of the following molecules: dichloro terpyridine platinum, concentration C = 350 muM, betamethasone and deoxyglucose with concentrations of C = 0.2 muM and C = 6 mM, respectively. The cells were subsequently irradiated by carbon C(6+) ion 290 MeV/amu up to a dose of 2.5 Gy, under atmospheric conditions.Results: The presence of the platinum salt or bethamethasone augments the cell death rate. The combination of betamethasone with the platinum salt also increases the cell death rate, but less than for the platinum salt alone. The explanation is that any radiosensitizer also behaves as a scavenger of free radicals. This dual behavior should be considered in any optimization of the design of radiosensitizers when different ionizing particles are used.
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Villemagne, B., Machelart A, Tran, N. C., Flipo M, Moune, M., Leroux F, Piveteau, C., Wohlkonig A, Wintjens, R., Li X, Gref R, Brodin P, Deprez, B., Baulard AR, & Willand, N. (2020). Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. (Vol. 6).
Résumé: Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug design and in vitro evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.
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