Ruxandra Gref

Metal–Organic Frameworks in Biomedicine

Metal Organic Frameworks in Biomedicine Patricia Horcajada,* Ruxandra Gref, Tarek Baati, Phoebe K. Allan, Guillaume Maurin, Patrick Couvreur, G erard F erey, Russell E. Morris, and Christian Serre* Institut Lavoisier, UMR CNRS 8180, Universit e de Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France Facult e de Pharmacie, UMR CNRS 8612, Universit e Paris-Sud, 92296 Châtenay-Malabry Cedex, France Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Universit e Montpellier 2, 34095 Montpellier cedex 05, France EaStChem School of Chemistry, University of St. Andrews Purdie Building, St Andrews, KY16 9ST U.K.

Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging

In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers. Most of the existing carrier materials show poor drug loading (usually less than 5 wt% of the transported drug versus the carrier material) and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier. In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications. Here we show that specific non-toxic porous iron(III)-based metal-organic frameworks with engineered cores and surfaces, as well as imaging properties, function as superior nanocarriers for efficient controlled delivery of challenging antitumoural and retroviral drugs (that is, busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) against cancer and AIDS. In addition to their high loadings, they also potentially associate therapeutics and diagnostics, thus opening the way for theranostics, or personalized patient treatments.

BioMOFs: Metal–Organic Frameworks for Biological and Medical Applications

The class of highly porous materials called metal-organic frameworks offer many opportunities for applications across biology and medicine. Their wide range of chemical composition makes toxicologically acceptable formulation possible, and their high level of functionality enables possible applications as imaging agents and as delivery vehicles for therapeutic agents. The challenges in the area encompass not only the development of new solids but also improvements in the formulation and processing of the materials, including tailoring the morphology and surface chemistry of the frameworks to fit the proposed applications.

Stealth PLA-PEG Nanoparticles as Protein Carriers for Nasal Administration

AbstractPurpose. The aim of the study was to encapsulate a model protein antigen, tetanus toxoid (TT), within hydrophobic (PLA) and surface hydrophilic (PLA-PEG) nanoparticles and to evaluate the potential of these colloidal carriers for the transport of proteins through the nasal mucosa. Methods. TT-loaded nanoparticles, prepared by a modified water-in-oil-in-water solvent evaporation technique, were characterized in their size, zeta potential and hydrophobicity. Nanoparticles were also assayed in vitro for their ability to deliver active antigen for extended periods of time. Finally, 125I-TT-loaded nanoparticles were administered intranasally to rats and the amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 48 h. Results. PLA and PLA-PEG nanoparticles had a similar particle size (137-156 nm) and negative surface charge, but differed in their surface hydrophobicity: PLA were more hydrophobic than PLA-PEG nanoparticles. PLA-PEG nanoparticles, especially those containing gelatine as an stabilizer, provided extended delivery of the active protein. The transport of the radiolabeled protein through the rat nasal mucosa was highly affected by the surface properties of the nanoparticles: PLA-PEG nanoparticles led to a much greater penetration of TT into the blood circulation and the lymph nodes than PLA nanoparticles. Furthermore, after administration of 125I-TT-loaded PLA-PEG nanoparticles, it was found that a high amount of radioactivity persisted in the blood compartment for at least 48 h. Conclusions. A novel nanoparticulate system has been developed with excellent characteristics for the transport of proteins through the nasal mucosa.

The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa

The influence of the surface characteristics of colloidal drug carriers in their interaction with different biological surfaces is becoming increasingly evident. In order to investigate the importance of these characteristics in their interaction with the ocular mucosa, we developed three types of nanocapsules that differ in their surface properties: poly- epsilon -caprolactone (PECL) nanocapsules, chitosan (CS)-coated PECL nanocapsules and poly(ethylene glycol) (PEG)-coated PECL nanocapsules. Two different approaches were used to form these polymer coated nanocapsules: (i) the electrostatic anchorage of the coating onto the PECL nanocapsules-in the case of CS-and (ii) the use of the previously synthesized copolymer PECL-PEG for the formation of the nanocapsules. In both cases, the systems, prepared by the interfacial deposition technique, were loaded with a fluorescent dye (rhodamine) in order to quantify and visualize their interaction with the ocular surface ex vivo and in vivo. An important conclusion from the ex vivo studies is that the developed systems, and specially the CS-coated ones, enhanced the penetration of the encapsulated dye through the cornea. This effect was not simple due to the physical presence of the nanocapsules but to their ability to carry the encapsulated compound. The second conclusion from the confocal laser scanning microscopy (CLSM) studies is that the systems were able to enter the corneal epithelium by a transcellular pathway and that the penetration rate was dependent on the coating composition. The images suggest that the PEG coating accelerates the transport of the nanocapsules across the whole epithelium, whereas the CS coating favours the retention of the nanocapsules in the superficial layers of the epithelium. The specific behaviour of CS-coated systems was also corroborated in vivo. These results indicate that the surface composition of colloidal drug carriers affects their biodistribution in the eye. Therefore, this surface modification approach can be used as a targeting strategy in ocular drug delivery.

Preparation and characterization of protein C-loaded PLA nanoparticles.

This paper deals with the preparation and the characterization of poly(lactic acid) (PLA) nanoparticles containing protein C, a plasma inhibitor. Nanoparticles were prepared by the double emulsion method (w/o/w), using methylene chloride as an organic solvent and polyvinyl alcohol (PVA) or human serum albumin (HSA) as a surfactant. The influence of experimental constraints such as sonication and organic solvent on protein C activity was evaluated. It appears that a short time of sonication as well as the addition of acetone to methylene chloride (1/1) limited the lost of protein C activity. The study of protein C adsorption on blank PLA nanoparticles gave evidence to hydrophobic interactions between these two entities. The increase in PLA molecular weight on the characteristics of the protein C-loaded nanoparticles led to both a slightly decreased particle size and a lower polydispersity index, whereas the entrapment efficiency of protein C was not affected. The use of HSA as a surfactant allowed the increase in the entrapment efficiency of protein C but prevented its release. Finally, the evaluation of the activity of released protein C clearly illustrates that it was disturbed during the nanoparticle preparation. Thus, the obtained results emphasize the potential of protein C-loaded biodegradable nanoparticles for protein progressive delivery in plasma.

Surface-engineered nanoparticles for multiple ligand coupling.

The design of surface-engineered nanoparticles for targeting to specific sites is a major challenge. To our knowledge, no study in the literature deals with ligand functionalization of biodegradable nanoparticles through biotin-avidin interactions. With the aim of conceiving small-sized nanoparticles which can be easily functionalized with a variety of ligands or mixtures thereof, biotinylated and PEGylated biotin-poly(ethylene glycol)-poly(epsilon-caprolactone) (B-PEG-PCL) copolymers were synthesized and used to prepare nanoparticles of around 100 nm. Avidin, followed by biotinylated wheat germ agglutinin as a model lectin, were coupled to their surface by taking advantage of the strong biotin-avidin complex formation. The cytotoxicity of the nanospheres towards Caco-2 cells in culture was negligible (more than 82% cell survival for nanoparticle concentrations up to 300 microg/well). The amount of radiolabeled poly(lactic acid) (PLA) or PEG-PLA nanoparticles associated with Caco-2 cells was only 0.7% and 1.5% of the amount added, respectively. This value was increased to 8.5% when a sufficient amount of lectin was bound to the PEG-PLA copolymer. After further studies, the biotin-PEG-coated nanoparticles could be helpful tools for studying the interaction between cells and functionalized nanoparticles with various surface characteristics (PEG layer density and thickness, ligand type and density).

Study of emulsion stabilization by graft copolymers using the optical analyzer Turbiscan

Oil-in-water nanoemulsions were prepared using a series of synthetic graft copolymers with a backbone of dextran (DEX) and a number of side chains of poly-epsilon-caprolactone (PCL). In this paper, we focus on the o/w emulsion stabilizing abilities of these novel PCL-DEX copolymers, using a recently developed optical analyzer (Turbiscan). The main advantage of Turbiscan is to detect the destabilization phenomena in non-diluted emulsion, much earlier than the naked eyes operator, especially in the case of an opaque and concentrated system. This study shows that PCL-DEX copolymers successfully stabilized ethyl acetate-in-water emulsions, even in the absence of additional surfactants, whereas they were not efficient in stabilizing methylene chloride-in-water emulsions which coalesced fast and irreversibly. The ethyl acetate-in-water emulsion stabilizing ability of PCL-DEX seemed to be related to the localization of their blocks with regard to the oil-water interface.

Cyclodextrins for drug delivery

Cyclodextrins (CDs) are macrocyclic oligosaccharides composed of α(1,4)-linked glucopyranose subunits. These molecules possess a cage-like supramolecular structure, comparable with the structures of crown ethers, cryptands, spherands, cyclophanes, or calixarenes. However, it took 50 years to establish the molecular structure of CDs. Owing to their capability to form inclusion complexes with a variety of guest molecules, CDs are considered as the most important supramolecular host family among all supramolecular structures mentioned above. They can form complexes with various types of molecules including inorganic, organic, or organometallic that can be radical, cationic, anionic, or neutral molecules. This phenomenon bears the name “molecular recognition,” while the selectivity in the formation of complexes with enantiomeric species as guests is called “chiral recognition.” In addition, the properties of the molecules forming the complexes with CDs can be modified significantly. As such, a large number of scientists have attempted to elaborate and evaluate various CD derivatives that are able to complex a variety of drugs, enhancing by this way their in vivo solubility and activity. Moreover, a large number of publications describe CD uses in other fields such as foods, textile, cosmetics, or agriculture. This review reports on the recent developments of CDs in drug delivery using various routes of administration.

Optimisation of the synthesis of MOF nanoparticles made of flexible porous iron fumarate MIL-88A

The synthesis of nanoparticles of the porous flexible iron fumarate MIL-88A (MIL stands for Materials from Institut Lavoisier) has been studied through the use of several synthetic routes using non-toxic solvents. Hydro-solvothermal synthesis under dynamic or static, ambient or autogenous pressure conditions, assisted or not by microwave irradiation or ultrasonic methods have been compared in terms of particle size, polydispersity and yield. Different parameters such as temperature, time, concentration, pH or the use of additives (base, inhibitor) were evaluated. The resulting nanoparticles were characterised using X-ray powder diffraction (XRPD), dynamic light scattering (DLS), transmission and scanning electron microscopy (TEM and SEM) and the yield of the reaction was estimated. Although significant amounts of small nanoparticles (∼200 nm) were obtained from each synthetic route, most conditions led to an important polydispersity. Ultrasonic synthesis led, on the contrary, to very low yields of small and monodisperse nanoparticles. Finally, only microwave assisted hydrothermal synthesis afforded the successful fast synthesis of high yields of small (<100 nm) and monodispersed nanoparticles.