Tania Hidalgo

Nanoscaled Zinc Pyrazolate Metal–Organic Frameworks as Drug-Delivery Systems

This work describes synthesis at the nanoscale of the isoreticular metal-organic framework (MOF) series ZnBDP_X, based on the assembly of Zn(II) metal ions and the functionalized organic spacers 1,4-bis(1H-pyrazol-4-yl)-2-X-benzene (H2BDP_X; X = H, NO2, NH2, OH). The colloidal stability of these systems was evaluated under different relevant intravenous and oral-simulated physiological conditions, showing that ZnBDP_OH nanoparticles exhibit good structural and colloidal stability probably because of the formation of a protein corona on their surface that prevents their aggregation. Furthermore, two antitumor drugs (mitroxantrone and [Ru(p-cymene)Cl2(pta)] (RAPTA-C) where pta = 1,3,5-triaza-7-phospaadamantane) were encapsulated within the pores of the ZnBDP_X series in order to investigate the effect of the framework functionalization on the incorporation/delivery of bioactive molecules. Thus, the loading capacity of both drugs within the ZnBDP_X series seems to directly depend on the surface area of the solids. Moreover, ligand functionalization significantly affects both the delivery kinetics and the total amount of released drug. In particular, ZnBDP_OH and ZnBDP_NH2 matrixes show a slower rate of delivery and higher percentage of release than ZnBDP_NO2 and ZnBDP_H systems. Additionally, RAPTA-C delivery from ZnBDP_OH is accompanied by a concomitant and progressive matrix degradation due to the higher polarity of the BPD_OH ligand, highlighting the impact of functionalization of the MOF cavities over the kinetics of delivery.

Heparin-engineered mesoporous iron metal-organic framework nanoparticles: toward stealth drug nanocarriers.

The specific modification of the outer surface of the promising porous metal-organic framework nanocarriers (nanoMOFs) preserving their characteristic porosity is still a major challenge. Here a simple, fast, and biofriendly method for the external functionalization of the benchmarked mesoporous iron(III) trimesate nanoparticles MIL-100(Fe) with heparin, a biopolymer associated with longer-blood circulation times is reported. First, the coated nanoparticles showed intact crystalline structure and porosity with improved colloidal stability under simulated physiological conditions, preserving in addition its encapsulation and controlled release capacities. The effect of the heparin coating on the nanoMOF interactions with the biological environment is evaluated through cell uptake, cytotoxicity, oxidative stress, cytokine production, complement activation, and protein adsorption analysis. These results confirmed that the heparin coating endowed the nanoMOFs with improved biological properties, such as reduced cell recognition, lack of complement activation, and reactive oxygen species production. Overall, the ability to coat the surface of the nanoMOFs using a simple and straight-forward approach could be taken as a way to enhance the versatility and, thus, the potential of porous MOF nanoparticles in biomedicine.

Understanding the Colloidal Stability of the Mesoporous MIL-100(Fe) Nanoparticles in Physiological Media

The colloidal and chemical stability of nanoparticles of the nontoxic and biodegradable iron(III) trimesate MIL-100(Fe) nanocarrier have been evaluated in the presence of a series of simulated physiological fluids for intravenous and oral administration. MIL-100(Fe) nanoparticles exhibit an appropriate colloidal stability and biodegradability, mainly dependent on both the nature of their physicochemical surface and the media composition, being a priori compatible with their biomedical use.

Chitosan-coated mesoporous MIL-100(Fe) nanoparticles as improved bio-compatible oral nanocarriers

Nanometric biocompatible Metal-Organic Frameworks (nanoMOFs) are promising candidates for drug delivery. Up to now, most studies have targeted the intravenous route, related to pain and severe complications; whereas nanoMOFs for oral administration, a commonly used non-invasive and simpler route, remains however unexplored. We propose here the biofriendly preparation of a suitable oral nanocarrier based on the benchmarked biocompatible mesoporous iron(III) trimesate nanoparticles coated with the bioadhesive polysaccharide chitosan (CS). This method does not hamper the textural/structural properties and the sorption/release abilities of the nanoMOFs upon surface engineering. The interaction between the CS and the nanoparticles has been characterized through a combination of high resolution soft X-ray absorption and computing simulation, while the positive impact of the coating on the colloidal and chemical stability under oral simulated conditions is here demonstrated. Finally, the intestinal barrier bypass capability and biocompatibility of CS-coated nanoMOF have been assessed in vitro, leading to an increased intestinal permeability with respect to the non-coated material, maintaining an optimal biocompatibility. In conclusion, the preservation of the interesting physicochemical features of the CS-coated nanoMOF and their adapted colloidal stability and progressive biodegradation, together with their improved intestinal barrier bypass, make these nanoparticles a promising oral nanocarrier.

In vitro biocompatibility of mesoporous metal (III; Fe, Al, Cr) trimesate MOF nanocarriers

The high porosity and versatile composition of the benchmarked mesoporous metal (Fe, Al, Cr) trimesate metal-organic frameworks (MIL-100(Fe, Al, Cr)) make them very promising solids in different strategic industrial and societal domains (separation, catalysis, biomedicine, etc.). In particular, MIL-100(Fe) nanoparticles (NPs) have been recently revealed to be one of the most promising and innovative next generation tools enabling multidrug delivery to overcome cancer resistance. Here, we analyzed the in vitro toxicity of the potential drug nanocarrier MIL-100(Fe) NPs and the effect of the constitutive cation by comparing its cytotoxicity with that one of its Cr and Al analogue NPs. Lung (A549 and Calu-3) and hepatic (HepG2 and Hep3B) cell lines were selected considering pulmonary, ingestion or intravenous exposure modes. First, the complete physicochemical characterization (structural, chemical and colloidal stability) of the MIL-100(Fe, Al, Cr) NPs was performed in the cell culture media. Then, their cytotoxicity was evaluated in the four selected cell lines using a combination of methods from cell impedance, cell survival/death and ROS generation to DNA damage for measuring genotoxicity. Thus, MIL-100(Fe, Al, Cr) NPs did not induce in vitro cell toxicity, even at high doses in the p53 wild type cell lines (A549 and calu-3 (lung) and HepG2 (liver)). The only toxic effect of MIL100-Fe was observed in the hepatocarcinoma cell line Hep3B, which is stress sensitive because it does not express TP53, the guardian of the genome.

Crystal structure dependent in vitro antioxidant activity of biocompatible calcium gallate MOFs

Two novel 3-D coordination polymers, denoted MIL-155 and MIL-156 (MIL stands for Materials Institute Lavoisier), built up from calcium and the naturally occurring gallic acid (H4gal), have been hydrothermally synthesized and their crystal structures were determined by single-crystal X-ray diffraction. These solids are based on different inorganic subunits: infinite chains of edge-sharing dimers of CaO7 polyhedra linked through partially deprotonated gallate ligands (H2gal2-) for MIL-155 or [Ca2(H2O)(H2gal)2]·2H2O, and ribbon-like inorganic subunits containing both eight-fold or six-fold coordinated CaII ions linked through fully deprotonated gallate ligands (gal4-) for MIL-156 or [Ca3K2(H2O)2(gal)2]·nH2O (n∼ 5). Both solids contain small channels filled with water molecules, with, however no accessible porosity towards N2 at 77 K. MIL-155 and MIL-156 were proven to be biocompatible, as evidenced by in vitro assays (viability and cell proliferation/death balance). While the high chemical stability of MIL-156 makes it almost bioinert, the progressive degradation of MIL-155 leads to an important protective antioxidant effect, associated with the release of the bioactive gallate ligand.

GraftFast Surface Engineering to Improve MOF Nanoparticles Furtiveness

Controlling the outer surface of nanometric metal-organic frameworks (nanoMOFs) and further understanding the in vivo effect of the coated material are crucial for the convenient biomedical applications of MOFs. However, in most studies, the surface modification protocol is often associated with significant toxicity and/or lack of selectivity. As an alternative, how the highly selective and general grafting GraftFast method leads, through a green and simple process, to the successful attachment of multifunctional biopolymers (polyethylene glycol (PEG) and hyaluronic acid) on the external surface of nanoMOFs is reported. In particular, effectively PEGylated iron trimesate MIL-100(Fe) nanoparticles (NPs) exhibit suitable grafting stability and superior chemical and colloidal stability in different biofluids, while conserving full porosity and allowing the adsorption of bioactive molecules (cosmetic and antitumor agents). Furthermore, the nature of the MOF-PEG interaction is deeply investigated using high-resolution soft X-ray spectroscopy. Finally, a cell penetration study using the radio-labeled antitumor agent gemcitabine monophosphate (3 H-GMP)-loaded MIL-100(Fe)@PEG NPs shows reduced macrophage phagocytosis, confirming a significant in vitro PEG furtiveness.

Toward Understanding Drug Incorporation and Delivery from Biocompatible Metal–Organic Frameworks in View of Cutaneous Administration

Although metal–organic frameworks (MOFs) have widely demonstrated their convenient performances as drug-delivery systems, there is still work to do to fully understand the drug incorporation/delivery processes from these materials. In this work, a combined experimental and computational investigation of the main structural and physicochemical parameters driving drug adsorption/desorption kinetics was carried out. Two model drugs (aspirin and ibuprofen) and three water-stable, biocompatible MOFs (MIL-100(Fe), UiO-66(Zr), and MIL-127(Fe)) have been selected to obtain a variety of drug–matrix couples with different structural and physicochemical characteristics. This study evidenced that the drug-loading and drug-delivery processes are mainly governed by structural parameters (accessibility of the framework and drug volume) as well as the MOF/drug hydrophobic/hydrophilic balance. As a result, the delivery of the drug under simulated cutaneous conditions (aqueous media at 37 °C) demonstrated that these systems fulfill the requirements to be used as topical drug-delivery systems, such as released payload between 1 and 7 days. These results highlight the importance of the rational selection of MOFs, evidencing the effect of geometrical and chemical parameters of both the MOF and the drug on the drug adsorption and release.

Chitosan-engineered metal–organic frameworks as oral drug nanocarriers

Patricia Horcajada1, Tania Hidalgo2, Monica Gimenez-Marques2, Rosana Simon-Vazquez3, Jose Avila4, Maria C Asensio5, Fabrice Salles6, Christian Serre2, Africa Gonzalez-Fernandez3 1IMDEA Energy, Mostoles-madrid, Spain, 2Institut Lavoisier, CNRS UMR 8180, Versailles, France, 3Immunology, Biomedical Research Center (CINBIO) and Institute of Biomedical Research of Vigo (IBIV), Universidad de Vigo, Vigo, Spain, 4Synchrotron SOLEIL & Université Paris-Saclay, Gif-sur-Yvette Cedex, France, 5Synchrotron SOLEIL & Université Paris-Saclay, Gif Sur Yvette, France, 6ICGM UMR5253Equipe AIME, Université Montpellier II, Montpellier, France E-mail: patricia.horcajada@imdea.org