2021 |
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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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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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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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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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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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2020 |
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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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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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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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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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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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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2019 |
Perez-Lloret M, Fraix A, Petralia S, Conoci, S., Tafani V, Cutrone, G., Vargas-Berenguel, A., Gref R, & Sortino S. (2019). One-Step Photochemical Green Synthesis of Water-Dispersible Ag, Au, and Au@Ag Core-Shell Nanoparticles. Chemistry, 25(64), 14638.
Résumé: A simple and green synthetic protocol for the rapid and effective preparation of Ag, Au and Au@Ag core-shell nanoparticles (NPs) is reported based on the light irradiation of a biocompatible, water-soluble dextran functionalized with benzophenone (BP) in the presence of AgNO3 , HAuCl4 , or both. Photoactivation of the BP moiety produces the highly reducing ketyl radicals through fast (<50 ns) intramolecular H-abstraction from the dextran scaffold, which, in turn, ensures excellent dispersibility of the obtained metal NPs in water. The antibacterial activity of the AgNPs and the photothermal action of the Au@Ag core-shell are also shown.
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Cutrone G, Q. J., Menendez-Miranda M, Casas-Solvas JM, Aykaç A, Li X, Foulkes D, Moreira-Alvarez B, Encinar JR, Ladavière C, Desmaële D, Vargas-Berenguel A, Gref R. (2019). Comb-like dextran copolymers: A versatile strategy to coat highly porous MOF nanoparticles with a PEG shell. Carbohydr Polym, 223, 115085.
Résumé: Nanoparticles made of metal-organic frameworks (nanoMOFs) are becoming of increasing interest as drug carriers. However, engineered coatings such as poly(ethylene glycol) (PEG) based ones are required to prevent nanoMOFs recognition and clearance by the innate immune system, a prerequisite for biomedical applications. This still presents an important challenge due to the highly porous structure and degradability of nanoMOFs. We provide here a proof of concept that the surface of iron-based nanoMOFs can be functionalized in a rapid, organic solvent-free and non-covalent manner using a novel family of comb-like copolymers made of dextran (DEX) grafted with both PEG and alendronate (ALN) moieties, which are iron complexing groups to anchor to the nanoMOFs surface. We describe the synthesis of DEX-ALN-PEG copolymers by click chemistry, with control of both the amount of PEG and ALN moieties. Stable DEX-ALN-PEG coatings substantially decreased their internalization by macrophages in vitro, providing new perspectives for biomedical applications.
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Jain-Beuguel C, Li, X., Houel-Renault, L., Modjinou T, Gref R, Renard, E., & Langlois V. (2019). Water-Soluble Poly(3-hydroxyalkanoate) Sulfonate: Versatile Biomaterials Used as Coatings for Highly Porous Nano-Metal Organic Framework. (Vol. 20).
Résumé: Water-soluble poly(3-hydroxyalkanoate) containing ionic groups were designed by two successive photoactivated thiol-ene reactions. Sodium-3-mercapto-1-ethanesulfonate (SO3(-)) and poly(ethylene glycol) (PEG) methyl ether thiol were grafted onto poly(3-hydroxyoctanoate-co-3-hydroxyundecenoate) PHO(67)U(33) to introduce both ionic groups and hydrophilic moieties. The grafted copolymers PHO(67)SO3(-)(20)PEG(13) were then used as biocompatible coatings of nano-metal organic frameworks (nanoMOFs) surfaces. Scanning electron microscopy and scanning transmission electron microscopy coupled with energy dispersive X-ray characterizations have clearly demonstrated the presence of the copolymer on the MOF surface. These coated nanoMOFs are stable in aqueous and physiological fluids. Cell proliferation and cytotoxicity tests performed on murine macrophages J774.A1 revealed no cytotoxic side effect. Thus, biocompatibility and stability of these novel hybrid porous MOF structures encourage their use in the development of effective therapeutic nanoparticles.
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Jain-Beuguel, C., Li, X., Houel-Renault, L., Modjinou, T., Simon-Colin, C., Gref, R., Renard E, & Langlois V. (2019). Water-Soluble Poly(3-hydroxyalkanoate) Sulfonate: Versatile Biomaterials Used as Coatings for Highly Porous Nano-Metal Organic Framework. (Vol. 20).
Résumé: Water-soluble poly(3-hydroxyalkanoate) containing ionic groups were designed by two successive photoactivated thiol-ene reactions. Sodium-3-mercapto-1-ethanesulfonate (SO3(-)) and poly(ethylene glycol) (PEG) methyl ether thiol were grafted onto poly(3-hydroxyoctanoate-co-3-hydroxyundecenoate) PHO(67)U(33) to introduce both ionic groups and hydrophilic moieties. The grafted copolymers PHO(67)SO3(-)(20)PEG(13) were then used as biocompatible coatings of nano-metal organic frameworks (nanoMOFs) surfaces. Scanning electron microscopy and scanning transmission electron microscopy coupled with energy dispersive X-ray characterizations have clearly demonstrated the presence of the copolymer on the MOF surface. These coated nanoMOFs are stable in aqueous and physiological fluids. Cell proliferation and cytotoxicity tests performed on murine macrophages J774.A1 revealed no cytotoxic side effect. Thus, biocompatibility and stability of these novel hybrid porous MOF structures encourage their use in the development of effective therapeutic nanoparticles.
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Jian Xu, L. W., Tao Guo, Guoqing Zhang, Caifen Wang, Haiyan Li, Xue Li, Vikramjeet Singh, Weidong Chen, Ruxandra Gref, Jiwen Zhang. (2019). A “Ship-in-a-Bottle” strategy to create folic acid nanoclusters inside the nanocages of gamma-cyclodextrin metal-organic frameworks. Int J Pharm, 556, 89.
Résumé: Assembled between gamma-cyclodextrins (CD) and potassium ions, gamma-cyclodextrin metal-organic frameworks (CD-MOF) create spatially extended and ordered cage-like structures. Herein, it was demonstrated that folic acid (FA), a model molecule, could be densely packed inside CD-MOF reaching 2:1 FA:CD molar ratio. This “Ship-in-a-Bottle” strategy leads to a 1450 fold increase of the apparent solubility of FA. Moreover, the bioavailability of FA inside CD-MOF in rats was enhanced by a factor of 1.48 as compared to free FA. The unique mechanism of FA incorporation in the CD-MOF 3D network was also explored, which was different from the conventional CD inclusion complexation. Taylor dispersion investigations indicated that FA was incorporated on the basis of a two-component model, which was further supported by a set of complementary methods, including SEM, XRPD, BET, SR-FTIR, SAXS and molecular simulation. The hypothesized mechanism suggested that: i) tiny FA nanoclusters formed inside the hydrophilic cavities and onto the surface of CD-MOF and ii) FA was included inside dual-CD units in CD-MOF. In a nutshell, this dual incorporation mechanism is an original approach to dramatically increase the drug apparent solubility and bioavailability, and could be a promising strategy for other poorly soluble drugs.
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Li, X., Semiramoth, N., Hall, S., Tafani, V., Josse, J., Laurent, F., Salzano, G., Foulkes, D., Brodin, P., Majlessi, L., Ghermani, N. ‐E., Maurin, G., Couvreur, P., Serre, C., Bernet‐Camard, M. ‐F., Zhang, J., & Gref, R. (2019). Combinatorial Drug Therapy: Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections (Part. Part. Syst. Charact. 3/2019). Part. Part. Syst. Charact., 36(3), 1970009.
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Li, X., Semiramoth, N., Hall, S., Tafani, V., Josse, J., Laurent, F., Salzano, G., Foulkes, D., Brodin, P., Majlessi, L., Ghermani, N. ‐E., Maurin, G., Couvreur, P., Serre, C., Bernet‐Camard, M. ‐F., Zhang, J., & Gref, R. (2019). Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections. Part. Part. Syst. Charact., 36(3), 1800360.
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Pastor A,, Machelart A,, Li X,, Willand N,., Baulard A, Brodin, P., Gref R, & Desmaele D. (2019). A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation. (Vol. 17).
Résumé: Ethionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of molecules called “boosters” among which BDM43266 is one of the most potent. However, the co-administration of these active molecules is hampered by their low solubility in biological media and by the strong tendency of ETH to crystallize. A novel strategy that involves synthesizing a codrug able to self-associate into nanoparticles prone to be taken up by infected macrophages is proposed here. This codrug is designed by tethering N-hydroxymethyl derivatives of both ETH and its booster through a glutaric linker. This codrug self-assembles into nanoparticles of around 200 nm, stable upon extreme dilution without disaggregating as well as upon concentration. The nanoparticles of the codrug can be intranasally administered overcoming the unfavorable physico-chemical profiles of the parent drugs. Intrapulmonary delivery of the codrug nanoparticles to Mtb infected mice via the intranasal route at days 7, 9, 11, 14, 16 and 18 post-infection reduces the bacterial load in the lungs by a factor of 6.
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Porcino, M., Christodoulou, I., Vuong, M. D. L., Gref, R., & Martineau-Corcos, C. (2019). New insights on the supramolecular structure of highly porous core–shell drug nanocarriers using solid-state NMR spectroscopy. RSC Adv., 9(56), 89.
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Shailendra Shakya, Y. H., Xiaohong Ren, Tao Guo, Abi Maharjan, Ting Luo, Tingting Wang, Ramesh Dhakhwa, Balmukunda Regmi, Haiyan Li, Ruxandra Gref, Jiwen Zhang. (2019). Ultrafine Silver Nanoparticles Embedded in Cyclodextrin Metal-Organic Frameworks with GRGDS Functionalization to Promote Antibacterial and Wound Healing Application. (Vol. 15).
Résumé: The challenge of bacterial infection increases the risk of mortality and morbidity in acute and chronic wound healing. Silver nanoparticles (Ag NPs) are a promising new version of conventional antibacterial nanosystem to fight against the bacterial resistance in concern of the drug discovery void. However, there are several challenges in controlling the size and colloidal stability of Ag NPs, which readily aggregate or coalesce in both solid and aqueous state. In this study, a template-guided synthesis of ultrafine Ag NPs of around 2 nm using water-soluble and biocompatible gamma-cyclodextrin metal-organic frameworks (CD-MOFs) is reported. The CD-MOF based synthetic strategy integrates AgNO3 reduction and Ag NPs immobilization in one pot achieving dual functions of reduced particle size and enhanced stability. Meanwhile, the synthesized Ag NPs are easily dispersible in aqueous media and exhibit effective bacterial inhibition. The surface modification of cross-linked CD-MOF particles with GRGDS peptide boosts the hemostatic effect that further enhances wound healing in synergy with the antibacterial effect. Hence, the strategy of ultrafine Ag NPs synthesis and immobilization in CD-MOFs together with GRGDS modification holds promising potential for the rational design of effective wound healing devices.
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Yuanzhi He, W. Z., Tao Guo, Guoqing Zhang, Wei Qin, Liu Zhang, Caifen Wang, Weifeng Zhu, Ming Yang, Xiaoxiao Hu, Vikramjeet Singh, Li Wu, Ruxandra Gref, Jiwen Zhang. (2019). Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan. Acta Pharm Sin B, 9(1), 97.
Résumé: Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile gamma-cyclodextrin (gamma-CD) metal-organic framework (CD-MOF) large molecular cages in which azilsartan (AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague-Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering (SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the gamma-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7nm sized cavity surrounded by six gamma-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.
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2017 |
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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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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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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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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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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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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2016 |
Conte, C., Fotticchia, I., Tirino, P., Moret, F., Pagano, B., Gref, R., Ungaro, F., Reddi, E., Giancola, C., & Quaglia, F. (2016). Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate. Colloids And Surfaces B-Biointerfaces, 141, 148–157.
Résumé: In the last decades, nano-oncologicals bearing a polyethylene glycol (PEG) coating are being emerging as biomimetic devices able to drive their drug cargo to solid tumors through passive mechanisms. To improve selectivity toward cancer cells, nanocarriers decorated with the small ligand folate have been widely investigated. Nevertheless, a great challenge remains the effective exposition of folate on nanoparticles (NPs), which is a key prerequisite to ensure the correct binding to receptor and the following endocytic uptake. On these premises, in this study we propose a novel strategy to produce core-shell folate-targeted NPs based on diblock copolymers of poly(epsilon-caprolactone) (PCL) and PEG through the aid of (2-hydroxypropyl)-beta-cyclodextrin (HPPCD). PCL4300-PEG(2000) and PCL4300-PEG(2000)-Fol copolymers were synthesized, characterized and employed to produce NPs without and with HP beta CD by a melting/sonication procedure. Colloidal properties of targeted NPs produced with HP beta CD demonstrated a highly extended conformation of PEG chains in the shell, an enhanced interaction with a specific antibody against folate and a higher uptake in cells overexpressing folate receptor. Overall, these results suggest that proper manipulation of PEG shell conformation through HP beta CD can represent a novel non-covalent strategy to modify shell features. (C) 2016 Elsevier B.V. All rights reserved.
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Ding, J. X., Cheng, Y. L., Li, M. Q., Gref, R., & Chen, X. S. (2016). Smart Polymeric Nanocarriers. Journal Of Nanomaterials, .
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Duchene, D., & Gref, R. (2016). Small is beautiful: Surprising nanoparticles. International Journal Of Pharmaceutics, 502(1-2), 219–231.
Résumé: In the preparation of nanoparticles for drug delivery, it is well known that their size as well as their surface decorations can play a major role in interaction with living media. It is less known that their shape and internal structure can interplay with cellular and in vivo fate. The scientific literature is full of a large variety of surprising terms referring to their shape and structure. The aim of this review is to present some examples of the most often encountered surprising nanoparticles prepared and usable in the pharmaceutical technology domain. They are presented in two main groups related to their physical aspects: 1) smooth surface particles, such as Janus particles, “snowmen”, “dumbbells”, “rattles”, and “onions” and 2) branched particles, such as “flowers”, “stars” and “urchins”. The mode of preparation and potential applications are briefly presented. The topic has a serious, wider importance, namely in opportunity these structures have to allow exploration of the role of shape and structure on the utility (and perhaps toxicity) of these nanostructures. (C) 2016 Elsevier B.V. All rights reserved.
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Duchene, D., Cavalli, R., & Gref, R. (2016). Cyclodextrin-based Polymeric Nanoparticles as Efficient Carriers for Anticancer Drugs. Current Pharmaceutical Biotechnology, 17(3), 248–255.
Résumé: Among the difficulties encountered in the treatment of cancer are the physico-chemical properties of the chemotherapeutic agents; in particular low water solubility and low stability, resulting in poor efficacy. Due to their capability to form molecular inclusions with apolar molecules (or part of them) cyclodextrins constitute a powerful tool to prepare more efficient chemotherapeutic delivery systems such as nanoparticles. This review focuses on polymeric nanoparticles for cancer therapy prepared from either cyclodextrin molecules, or polymer and cyclodextrins.
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Liu, B. T., Li, H. Y., Xu, X. N., Li, X., Lv, N. N., Singh, V., Stoddart, J. F., York, P., Xu, X., Gref, R., & Zhang, J. W. (2016). Optimized synthesis and crystalline stability of gamma-cyclodextrin metal-organic frameworks for drug adsorption. International Journal Of Pharmaceutics, 514(1), 212–219.
Résumé: The biocompatible and renewable cyclodextrin metal-organic frameworks (CD-MOFs) have addressed a range of opportunities in molecular storage and separation sciences. The reported protocols for their synthesis, however, were carried out at room temperature over long time periods of time (24 h), producing crystals of relatively poor uniformity. In this investigation, micron sized gamma-CD-MOFs were synthesized by an optimized vapor diffusion method at elevated temperature (50 degrees C) within 6 h, after which the size control, crystalline stability and drug adsorption behavior were investigated in detail. In this manner, uniform cubic gamma-CD-MOF crystals were obtained when the reaction temperature was raised to 50 degrees C with pre-addition of the reaction solvent. The size of gamma-CD-MOFs was adjusted efficiently by changing the reactant concentrations, temperatures, time, gamma-CD ratios to KOH and surfactant concentrations, without influencing the porosity and crystallinity of the material markedly. Varing degrees of reduction in crystallinity and change in morphology were observed when the gamma-CD-MOF crystals are treated under conditions of high temperature (100 degrees C), high humidity (92.5%) and polar solvents (e.g., MeOH and DMF). In relation to drug adsorption by gamma-CD-MOFs, most of the drug molecules containing carboxyl groups showed relatively high adsorption (> 5%), while low adsorption (< 5%) was found for drugs with nitrogen-containing heterocyclic rings. In addition, the adsorption kinetics of captopril to standard gamma-CD-MOFs matched a pseudo-second-order model rather well, whilst captopril adsorption to the damaged gamma-CD-MOFs only partially matched the pseudo-second-order model. In summary, based upon the optimized synthesis and size control of gamma-CD-MOFs, the crystalline stability and drug adsorption characteristics of gamma-CD-MOF crystals have been evaluated as a fundamental requirement of a potential vehicle for drug delivery. (C) 2016 Elsevier B.V. All rights reserved.
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Simon-Yarza, M. T., Baati, T., Paci, A., Lesueur, L. L., Seck, A., Chiper, M., Gref, R., Serre, C., Couvreur, P., & Horcajada, P. (2016). Antineoplastic busulfan encapsulated in a metal organic framework nanocarrier: first in vivo results. Journal Of Materials Chemistry B, 4(4), 585–588.
Résumé: Nanoparticles of a mesoporous iron(III) trimesate MIL-100 nanocarrier encapsulating high amounts of the challenging antineoplastic busulfan were administered to rats and compared with the commercial Busilvex (R). Large differences in serum concentration of both busulfan and trimesate revealed the great impact of drug encapsulation both on the drug and on nanoparticle pharmacokinetics during the first 24 h of administration.
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Simon-Yarza, T., Baati, T., Neffati, F., Njim, L., Couvreur, P., Serre, C., Gref, R., Najjar, M. F., Zakhama, A., & Horcajada, P. (2016). In vivo behavior of MIL-100 nanoparticles at early times after intravenous administration. International Journal Of Pharmaceutics, 511(2), 1042–1047.
Résumé: Metal-organic frameworks have shown interesting features for biomedical applications, such as drug delivery and imaging agents. The benchmarked mesoporous iron(III) trimesate MIL-100 MOF nanocarrier combines progressive release of high drug cargoes with absence of visible in vivo toxicity. Although in a previous study pharmacokinetics and biodistribution of MIL-100 nanoparticles were evaluated in the long term (from 24h to 1 month), the crucial times for drug targeting and delivery applications are shorter (up to 24 h). Thus, this work aims to study the blood circulating profile and organ accumulation of MIL-100 nanocarrier at early times after administration. For this purpose, after intravenous administration to rats, both constitutive components of MIL-100 (trimesate and iron) were quantified by high performance liquid chromatography and a spectrophotometric method, respectively. The pharmacokinetic profile suggested that the nanoparticles act as a depot in the blood stream during the first hours before being cleared. Accumulation took mainly place in the liver and, in some extent, in the spleen. Nevertheless, histological studies demonstrated the absence of morphological alterations due to the presence of the particles in these organs. Liver function was however slightly altered as reflected by the increased plasma aspartate aminotransferase concentrations. Finally trimesate was progressively eliminated in urine. (C) 2016 Elsevier B.V. All rights reserved.
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2015 |
Abed, N., Said-Hassane, F., Zouhiri, F., Mougin, J., Nicolas, V., Desmaele, D., Gref, R., & Couvreur, P. (2015). An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance. Scientific Reports, 5.
Résumé: The “Golden era” of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55-63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells.
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Agostoni, V., Horcajada, P., Noiray, M., Malanga, M., Aykac, A., Jicsinszky, L., Vargas-Berenguel, A., Semiramoth, N., Daoud-Mahammed, S., Nicolas, V., Martineau, C., Taulelle, F., Vigneron, J., Etcheberry, A., Serre, C., & Gref, R. (2015). A “green” strategy to construct non-covalent, stable and bioactive coatings on porous MOF nanoparticles. Scientific Reports, 5, 7925.
Résumé: Nanoparticles made of metal-organic frameworks (nanoMOFs) attract a growing interest in gas storage, separation, catalysis, sensing and more recently, biomedicine. Achieving stable, versatile coatings on highly porous nanoMOFs without altering their ability to adsorb molecules of interest represents today a major challenge. Here we bring the proof of concept that the outer surface of porous nanoMOFs can be specifically functionalized in a rapid, biofriendly and non-covalent manner, leading to stable and versatile coatings. Cyclodextrin molecules bearing strong iron complexing groups (phosphates) were firmly anchored to the nanoMOFs' surface, within only a few minutes, simply by incubation with aqueous nanoMOF suspensions. The coating procedure did not affect the nanoMOF porosity, crystallinity, adsorption and release abilities. The stable cyclodextrin-based coating was further functionalized with: i) targeting moieties to increase the nanoMOF interaction with specific receptors and ii) poly(ethylene glycol) chains to escape the immune system. These results pave the way towards the design of surface-engineered nanoMOFs of interest for applications in the field of targeted drug delivery, catalysis, separation and sensing.
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Fraix, A., Kandoth, N., Gref, R., & Sortino, S. (2015). A Multicomponent Gel for Nitric Oxide Photorelease with Fluorescence Reporting. Asian Journal Of Organic Chemistry, 4(3), 256–261.
Résumé: An engineered hydrogel platform has been developed, in the absence of any toxic solvents or reagents, by the supramolecular self-assembly of three different components: a poly--cyclodextrin polymer, a hydrophobically modified dextran, and a photoactivatable bichromophoric molecular conjugate designed to photorelease nitric oxide (NO) with a fluorescent reporting function. The multivalent character of the interactions between the all components and the poor solubility of the conjugate in aqueous medium ensure the stability of the hydrogel and the lack of leaching of the photoactive cargo from the gel network under physiological conditions, even in the absence of protective coating agents. The photochemical properties of the molecular conjugate are retained in the supramolecular matrix, as demonstrated by the remote-controlled release of NO upon visible light excitation simultaneously to the activation of a fluorescent reporting function, which allows easy monitoring of the photoreleased NO.
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Ladaviere, C., & Gref, R. (2015). Toward an optimized treatment of intracellular bacterial infections: input of nanoparticulate drug delivery systems. Nanomedicine, 10(19), 3033–3055.
Résumé: Intracellular pathogenic bacteria can lead to some of the most life-threatening infections. By evolving a number of ingenious mechanisms, these bacteria have the ability to invade, colonize and survive in the host cells in active or latent forms over prolonged period of time. A variety of nanoparticulate systems have been developed to optimize the delivery of antibiotics. Main advantages of nanoparticulate systems as compared with free drugs are an efficient drug encapsulation, protection from inactivation, targeting infection sites and the possibility to deliver drugs by overcoming cellular barriers. Nevertheless, despite the great progresses in treating intracellular infections using nanoparticulate carriers, some challenges still remain, such as targeting cellular subcompartments with bacteria and delivering synergistic drug combinations. Engineered nanoparticles should allow controlling drug release both inside cells and within the extracellular space before reaching the target cells.
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Nie, S. Y., Zhang, X. F., Gref, R., Couvreur, P., Qian, Y., & Zhang, L. J. (2015). Multilamellar Nanoparticles Self-Assembled from Opposite Charged Blends: Insights from Mesoscopic Simulation. Journal Of Physical Chemistry C, 119(35), 20649–20661.
Résumé: Multi lamellar nanoparticles (NPs) are spontaneously formed when mixing two components with opposite charges, meaningful for drug delivery. However, details of NPs association and mechanisms of this process remain largely unknown, due to the limitation of experimental technique. In this work, we use dissipative particle dynamics (DPD) simulation for the first time to determine the structure property relationships of multilamellar NPs formed by charged blends. As a case study, a system with polyanionic fondparinux (Fpx) and cationic derivatives squalenoyl (CSq, including Sql(+) and Sq(++)) in aqueous media is investigated, with a focus on the optimized formation condition and mechanism of regular spherical multilamellar NPs. In particular, we find that highly ordered multilamellar structures tend to form when the nonbonded interaction between Fpx CSq and hydrophobic interaction contributed by CSq are well-balanced. The DPD results strongly agree with corresponding experimental results of this novel nanoparticulate drug carrier. This study could help develop promising multilamellar NPs formed by charged blends through self-assembly for drug delivery.
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Ralay-Ranaivo, B., Borgel, D., Couvreur, P., & Gref, R. (2015). Trends in the development of oral anticoagulants. Therapeutic Delivery, 6(6), 685–703.
Résumé: Anticoagulation remains the therapy of choice for the prevention and treatment of venous and arterial thromboembolic disorders which can cause major organ damage or death. Heparins represent the antithrombotic drugs of choice in short and medium-term prophylaxis and therapy of thromboembolic diseases. Fondaparinux, a synthetic and structural analog of the antithrombin-binding pentasaccharide domain of heparin, has selective anti-Xa activity and longer half-life. However, anticoagulants are poorly absorbed by oral route because of their high molecular weight, hydrophilicity and negative charges. Long-term anticoagulation therapy is problematic because of side effects and frequent monitoring. Formulation approaches are particularly promising.
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Rodriguez-Ruiz, V., Maksimenko, A., Anand, R., Monti, S., Agostoni, V., Couvreur, P., Lampropoulou, M., Yannakopoulou, K., & Gref, R. (2015). Efficient “green” encapsulation of a highly hydrophilic anticancer drug in metal-organic framework nanoparticles. Journal Of Drug Targeting, 23(7-8), 759–767.
Résumé: Metal-organic frameworks (MOFs) are coordination polymers of interest for biomedical applications. Of particular importance, nanoparticles made of iron(III) trimesate (MIL-100, MIL standing for Material Institut Lavoisier) (nanoMOFs) can be conveniently synthesised under mild and green conditions. They were shown to be biodegradable, biocompatible and efficient to encapsulate a variety of active molecules. We have addressed here the challenges to encapsulate a highly hydrophilic anticancer prodrug, phosphated gemcitabin (Gem-MP) known for its instability and inability to bypass cell membranes. MIL-100 nanoMOFs acted as efficient “nanosponges”, soaking Gem-MP from its aqueous solution with almost perfect efficiency (>98%). Maximal loadings reached similar to 30 wt% reflecting the strong interaction between the drug and the iron trimesate matrices. Neither degradation nor loss of crystalline structure was observed after the loading process. Storage of the loaded nanoMOFs in water did not result in drug release over three days. However, Gem-MP was released in media containing phosphates, as a consequence to particle degradation. Drug-loaded nanoMOFs were effective against pancreatic PANC-1 cells, in contrast to free drug and empty nanoMOFs. However, an efflux phenomenon could contribute to reduce the efficacy of the nanocarriers. Size optimization and surface modification of the nanoMOFs are expected to further improve these findings.
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2014 |
Deshayes, S., & Gref, R. (2014). Synthetic and bioinspired cage nanoparticles for drug delivery. Nanomedicine, 9(10), 1545–1564.
Résumé: Nanotechnology has the potential to revolutionize drug delivery, but still faces some limitations. One of the main issues regarding conventional nanoparticles is their poor drug-loading and their early burst release. Thus, to overcome these problems, researchers have taken advantage of the host-guest interactions that drive some assemblies to form cage molecules able to strongly entrap their cargo and design new nanocarriers called cage nanoparticles. These systems can be classified into two categories: bioinspired nanosystems such as virus-like particles, ferritin, small heat shock protein: and synthetic host-guest supramolecular systems that require engineering to actually form supramolecular nanoassemblies. This review will highlight the recent advances in cage nanoparticles for drug delivery with a particular focus on their biomedical applications.
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Ralay-Ranaivo, B., Desmaele, D., Bianchini, E. P., Lepeltier, E., Bourgaux, C., Borgel, D., Pouget, T., Tranchant, J. F., Couvreur, P., & Gref, R. (2014). Novel self assembling nanoparticles for the oral administration of fondaparinux: Synthesis, characterization and in vivo evaluation. Journal Of Controlled Release, 194, 323–331.
Résumé: Fondaparinux (Fpx) is the anticoagulant of choice in the treatment of short- and medium-term thromboembolic disease. To overcome the low oral bioavailability of Fpx, a new nanoparticulate carrier has been developed. The nanoparticles (NPs) contain squalenyl derivatives, known for their excellent oral bioavailability. They spontaneously self-assemble upon both electrostatic and hydrophobic interactions between the polyanionic Fpx and cationic squalenyl (CSq) derivatives. The preparation conditions were optimized to obtain monodisperse, stable NPs with a mean diameter in the range of 150-200 nm. The encapsulation efficiencies were around 80%. Fpx loadings reached 39 wt.%. According to structural and morphological analysis, Fpx and CSq organized in spherical multilamellar (“onion-type”) nanoparticles. Furthermore, in vivo studies in rats suggested that Fpx was well absorbed from the orally administered NPs, which totally dissociated when reaching the blood stream, leading to the release of free Fpx. The Fpx: CSq NPs improved the plasmatic concentration of Fpx in a dose-dependent manner. However, the oral bioavailability of these new NPs remained low (around 0.3%) but of note, the C-max obtained after oral administration of 50 mg/kg NPs was close to the prophylactic plasma concentration needed to treat venous thromboembolism. Moreover, the oral bioavailability of Fpx could be dramatically increased up to 9% by including the nanoparticles into gastroresistant capsules. This study opens up new perspectives for the oral administration of Fpx and paves the way towards elaborating squalene-based NPs which self assemble without the need of covalently grafting the drug to Sq. (C) 2014 The Authors. Published by Elsevier B.V.
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