Metal-Organic Frameworks: Unconventional Nanoweapons against COVID.

The SARS-CoV-2 (COVID-19) pandemic outbreak led to enormous social and economic repercussions worldwide, felt even to this date, making the design of new therapies to combat fast-spreading viruses an imperative task. In the face of this, diverse cutting-edge nanotechnologies have risen as promising tools to treat infectious diseases such as COVID-19, as well as challenging illnesses such as cancer and diabetes. Aside from these applications, nanoscale metal-organic frameworks (nanoMOFs) have attracted much attention as novel efficient drug delivery systems for diverse pathologies. However, their potential as anti-COVID-19 therapeutic agents has not been investigated. Herein, we propose a pioneering anti-COVID MOF approach by studying their potential as safe and intrinsically antiviral agents through screening various nanoMOF. The iron(III)-trimesate MIL-100 showed a noteworthy antiviral effect against SARS-CoV-2 at the micromolar range, ensuring a high biocompatibility profile (90% of viability) in a real infected human cellular scenario. This research effectively paves the way toward novel antiviral therapies based on nanoMOFs, not only against SARS-CoV-2 but also against other challenging infectious and/or pulmonary diseases.

Nanoscaled metal-organic frameworks: charting a transformative path for cancer therapeutics and beyond.

Through this inspirational note, we would like to highlight the potential of nanoscaled metal-organic frameworks within the biomedical field. The unique properties of these materials that make them promising candidates for new nanomedicines are assessed here as well as the progression reached so far for combinational cancer therapies and theranostic, along with its most recent advances in nanomedicine. Finally, the perspective and challenges of these materials within this field is discussed.

Potential antiprostatic performance of novel lanthanide-complexes based on 5-nitropicolinic acid.

Two new lanthanide-complexes based on the 5-nitropicolinate ligand (5-npic) were obtained and fully characterized. Single-crystal X-ray diffraction revealed that these compounds are isostructural to a Dy-complex, previously published by us, based on dinuclear monomers link together with an extended hydrogen bond network, providing a final chemical formula of [Ln2(5-npic)6(H2O)4]·(H2O)2, where Ln = Dy (1), Gd (2), and Tb (3). Preliminary photoluminescent studies exhibited a ligand-centered emission for all complexes. The potential antitumoral activity of these materials was assayed in a prostatic cancer cell line (PC-3; the 2nd most common male cancerous disease), showing a significant anticancer activity (50-60% at 500 µg·mL-1). In turn, a high biocompatibility by both, the complexes and their precursors in human immunological HL-60 cells, was evidenced. In view of the strongest toxic effect in the tumoral cell line provided by the free 5-npic ligand (~ 40-50%), the overall anticancer complex performance seems to be triggered by the presence of this molecule.

Room Temperature Reduction of Nitrogen Oxide on Iron Metal-Organic Frameworks.

Nitrogen oxides represent one of the main threats for the environment. Despite decades of intensive research efforts, a sustainable solution for NOx removal under environmental conditions is still undefined. Using theoretical modelling, material design, state-of-the-art investigation methods and mimicking enzymes, it is found that selected porous hybrid iron(II/III) based MOF material are able to decompose NOx, at room temperature, in the presence of water and oxygen, into N2 and O2 and without reducing agents. This paves the way to the development of new highly sustainable heterogeneous catalysts to improve air quality.

Towards a More Efficient Breast Cancer Therapy Using Active Human Cell Membrane-Coated Metal-Organic Frameworks.

The recent description of well-defined molecular subtypes of breast cancer has led to the clinical development of a number of successful molecular targets. Particularly, triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with historically poor outcomes, mainly due to the lack of effective targeted therapies. Recent progresses in materials science have demonstrated the impressive properties of metal-organic framework nanoparticles (NPs) as antitumoral drug delivery systems. Here, in a way to achieve efficient bio-interfaces with cancer cells and improve their internalization, benchmarked MIL-100(Fe) NPs were coated with cell membranes (CMs) derived from the human TNBC cell line MDA-MB-468. The prepared CMs-coated metal-organic framework (CMs_MIL-100(Fe)) showed enhanced colloidal stability, cellular uptake, and cytotoxicity in MDA-MB-468 cells compared to non-coated NPs, paving the way for these human CMs-coated MIL-100(Fe) NPs as effective targeted therapies against the challenging TNBC.

Long-lasting insecticidal activity in plants driven by chlorogenic acid-loaded metal-organic frameworks.

Metal-organic frameworks (MOFs) possess a variety of interesting features related to their composition and structure that make them excellent candidates to be used in agriculture. However, few studies have reported their use as delivery agents of agrochemicals. In this work, the natural polyphenol chlorogenic acid (CGA) was entrapped via simple impregnation in the titanium aminoterephthalate MOF, MIL-125-NH2. A combination of experimental and computational techniques was used to understand and quantify the encapsulated CGA in MIL-125-NH2. Subsequently, CGA delivery studies were carried out in water at different pHs, showing a fast release of CGA during the first 2 h (17.3 ± 0.3% at pH = 6.5). In vivo studies were also performed against larvae of mealworm (Tenebrio molitor), evidencing the long-lasting insecticidal activity of CGA@MIL-125-NH2. This report demonstrates the potential of MOFs in the efficient release of agrochemicals, and paves the way to their study against in vivo models.

Proving the Antimicrobial Therapeutic Activity on a New Copper-Thiosemicarbazone Complex.

The misuse and overdose of antimicrobial medicines are fostering the emergence of novel drug-resistant pathogens, providing negative repercussions not only on the global healthcare system due to the rise of long-term or chronic patients and inefficient therapies but also on the world trade, productivity, and, in short, to the global economic growth. In view of these scenarios, novel action plans to constrain this antibacterial resistance are needed. Thus, given the proven antiproliferative tumoral and microbial features of thiosemicarbazone (TSCN) ligands, we have here synthesized a novel effective antibacterial copper-thiosemicarbazone complex, demonstrating both its solubility profile and complex stability under physiological conditions, along with their safety and antibacterial activity in contact with human cellular nature and two most predominant bacterial strains, respectively. A significant growth inhibition (17% after 20 h) is evidenced over time, paving the way toward an effective antibacterial therapy based on these copper-TSCN complexes.

Antibacterial Cu or Zn-MOFs Based on the 1,3,5-Tris-(styryl)benzene Tricarboxylate.

Metal-organic frameworks (MOFs) are highly versatile materials. Here, two novel MOFs, branded as IEF-23 and IEF-24 and based on an antibacterial tricarboxylate linker and zinc or copper cations, and holding antibacterial properties, are presented. The materials were synthesized by the solvothermal route and fully characterized. The antibacterial activity of IEF-23 and IEF-24 was investigated against Staphylococcus epidermidis and Escherichia coli via the agar diffusion method. These bacteria are some of the most broadly propagated pathogens and are more prone to the development of antibacterial resistance. As such, they represent an archetype to evaluate the efficiency of novel antibacterial treatments. MOFs were active against both strains, exhibiting higher activity against Staphylococcus epidermidis. Thus, the potential of the developed MOFs as antibacterial agents was proved.

Improving the genistein oral bioavailability via its formulation into the metal-organic framework MIL-100(Fe).

Despite the interesting chemopreventive, antioxidant and antiangiogenic effects of the natural bioflavonoid genistein (GEN), its low aqueous solubility and bioavailability make it necessary to administer it using a suitable drug carrier system. Nanometric porous metal-organic frameworks (nanoMOFs) are appealing systems for drug delivery. Particularly, mesoporous MIL-100(Fe) possesses a variety of interesting features related to its composition and structure, which make it an excellent candidate to be used as a drug nanocarrier (highly porous, biocompatible, can be synthesized as homogenous and stable nanoparticles (NPs), etc.). In this study, GEN was entrapped via simple impregnation in MIL-100 NPs achieving remarkable drug loading (27.1 wt%). A combination of experimental and computing techniques was used to achieve a deep understanding of the encapsulation of GEN in MIL-100 nanoMOF. Subsequently, GEN delivery studies were carried out under simulated physiological conditions, showing on the whole a sustained GEN release for 3 days. Initial pharmacokinetic and biodistribution studies were also carried out upon the oral administration of the GEN@MIL-100 NPs in a mouse model, evidencing a higher bioavailability and showing that this oral nanoformulation appears to be very promising. To the best of our knowledge, the GEN-loaded MIL-100 will be the first antitumor oral formulation based on nanoMOFs studied in vivo, and paves the way to the efficient delivery of nontoxic antitumorals via a convenient oral route.

A Robust and Biocompatible Bismuth Ellagate MOF Synthesized Under Green Ambient Conditions.

The first bioinspired microporous metal-organic framework (MOF) synthesized using ellagic acid, a common natural antioxidant and polyphenol building unit, is presented. Bi2O(H2O)2(C14H2O8)·nH2O (SU-101) was inspired by bismuth phenolate metallodrugs, and could be synthesized entirely from nonhazardous or edible reagents under ambient aqueous conditions, enabling simple scale-up. Reagent-grade and affordable dietary supplement-grade ellagic acid was sourced from tree bark and pomegranate hulls, respectively. Biocompatibility and colloidal stability were confirmed by in vitro assays. The material exhibits remarkable chemical stability for a bioinspired MOF (pH = 2-14, hydrothermal conditions, heated organic solvents, biological media, SO2 and H2S), attributed to the strongly chelating phenolates. A total H2S uptake of 15.95 mmol g-1 was recorded, representing one of the highest H2S capacities for a MOF, where polysulfides are formed inside the pores of the material. Phenolic phytochemicals remain largely unexplored as linkers for MOF synthesis, opening new avenues to design stable, eco-friendly, scalable, and low-cost MOFs for diverse applications, including drug delivery.

Phase-Selective Microwave Assisted Synthesis of Iron(III) Aminoterephthalate MOFs.

Iron(III) aminoterephthalate Metal-Organic Frameworks (Fe-BDC-NH2 MOFs) have been demonstrated to show potential for relevant industrial and societal applications (i.e., catalysis, drug delivery, gas sorption). Nevertheless, further analysis is required in order to achieve their commercial production. In this work, a systematic synthetic strategy has been followed, carrying out microwave (MW) assisted hydro/solvothermal reactions to rapidly evaluate the influence of different reaction parameters (e.g., time, temperature, concentration, reaction media) on the formation of the benchmarked MIL-101-NH2, MIL-88B-NH2, MIL-53-NH2 and MIL-68-NH2 solids. Characterization of the obtained solids by powder X-ray diffraction, dynamic light scattering and transmission electron microscopy allowed us to identify trends to the contribution of the evaluated parameters, such as the relevance of the concentration of precursors and the impact of the reaction medium on phase crystallization. Furthermore, we presented here for the first time the MW assisted synthesis of MIL-53-NH2 in water. In addition, pure MIL-101-NH2 was also produced in water while MIL-88-NH2 was the predominant phase obtained in ethanol. Pure phases were produced with high space-time yields, unveiling the potential of MW synthesis for MOF industrialization.

In deep evaluation of the neurotoxicity of orally administered TiO2 nanoparticles.

Titanium dioxide nanoparticles were widely used in food as dietary supplements, in drugs, in toothpaste, ect. Few numbers of studies were interested to the neurotoxicity of TiO2 NPs through oral pathway. The present study aims firstly to understand the connection between the physicochemical properties of TiO2 NPs and their associated toxicological oral pathway by evaluation the colloidal stability of TiO2 NPs over time in different media simulating physiological gastric, intestinal and serum conditions at 37 °C to be close to the oral administraton. Secondly, this study aims to evaluate the neurotoxicity of a subchronic intragastric administration of TiO2 NPs to rats. Different doses of anatase TiO2 NPs were administrated to Wistar rats every day for consecutives eight weeks. Titanium (Ti) content in brain, oxidative antioxidant biomarkers, lipid peroxidation, nitric oxide (NO) levels, tumor necrosis factor-alpha (TNF-α) levels, histophatological changes, degenerated and apoptosis neurons were investigated. Results suggested that TiO2 NPs can reach the brain and cross the brain blood barrier (BBB) to been accumulated in the brain of rats causing cerebral oxidative stress damage, increasing NO levels and histopathological injury. At higher dose, we observed the most cerebral injury by the highest accumulation of Ti and by the remarkable increase of TNF-α besides to the most increase of degenerated and apoptosis neurons in the brain of exposed rats. TiO2 NPs led to a neurotoxic damage accompanied by the increase of degenerated and apoptotic neurons in cerebral cortex.

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.

A Smart Metal-Organic Framework Nanomaterial for Lung Targeting.

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.

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.

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.

Extended and functionalized porous iron(III) tri- or dicarboxylates with MIL-100/101 topologies.

A series of nanometric isoreticular and/or functionalized analogues of the mesoporous environmentally-friendly iron(III) polycarboxylates MIL-100/101 have been successfully synthesized. Their exceptional pore size, of up to 68 Å, together with their relatively good stability in solvents, makes them promising candidates for heterogeneous catalysis or inclusion of large molecules, among others.

Cytotoxicity of nanoscaled metal-organic frameworks.

A series of fourteen porous Metal-Organic Frameworks (MOFs) with different compositions (Fe, Zn, and Zr; carboxylates or imidazolates) and structures have been successfully synthesised at the nanoscale and fully characterised by XRPD, FTIR, TGA, N2 porosimetry, TEM, DLS and ζ-potential. Their toxicological assessment was performed using two different cell lines: human epithelial cells from foetal cervical carcinoma (HeLa) and murine macrophage cell line (J774). It appears that MOF nanoparticles (NPs) exhibit low cytotoxicity, comparable to those of other commercialised nanoparticulate systems, the less toxic being the Fe carboxylate and the more toxic being the zinc imidazolate NPs. The cytotoxicity values, higher in J774 cells than in HeLa cells, are mainly function of their composition and cell internalisation capacity. Finally, cell uptake of one of the most relevant Fe-MOF-NPs for drug vectorisation has been investigated by confocal microscopy studies, and indicates a faster kinetics of cell penetration within J774 compared to HeLa cells.

Impact of phosphorylation on the encapsulation of nucleoside analogues within porous iron(iii) metal-organic framework MIL-100(Fe) nanoparticles.

Encapsulation of azidothymidine (AZT) or its phosphorylated derivatives (AZT-MP and AZT-TP) has been performed using nanoparticles of the porous crystalline iron(iii) trimesate metal-organic framework MIL-100(Fe). The number of phosphate groups per nucleoside analogue has a high impact on the drug loading capacity, and their interaction with the Lewis acid sites from the nanoMOFs is also discussed through a combination of techniques such as UV-vis absorption, circular dichroism, isothermal titration calorimetry, HPLC and molecular simulations. Finally, the effect of the differences in terms of host-guest interactions is discussed through the release in physiological buffers of AZT, AZT-MP and AZT-TP. New perspectives for the nanoencapsulation of monophosphorylated nucleoside analogues for effective anti-cancer and anti-viral therapies are then discussed.