Design of a Functionalized Metal-Organic Framework System for Enhanced Targeted Delivery to Mitochondria.

Mitochondria play a key role in oncogenesis and constitute one of the most important targets for cancer treatments. Although the most effective way to deliver drugs to mitochondria is by covalently linking them to a lipophilic cation, the in vivo delivery of free drugs still constitutes a critical bottleneck. Herein, we report the design of a mitochondria-targeted metal-organic framework (MOF) that greatly increases the efficacy of a model cancer drug, reducing the required dose to less than 1% compared to the free drug and ca. 10% compared to the nontargeted MOF. The performance of the system is evaluated using a holistic approach ranging from microscopy to transcriptomics. Super-resolution microscopy of MCF-7 cells treated with the targeted MOF system reveals important mitochondrial morphology changes that are clearly associated with cell death as soon as 30 min after incubation. Whole transcriptome analysis of cells indicates widespread changes in gene expression when treated with the MOF system, specifically in biological processes that have a profound effect on cell physiology and that are related to cell death. We show how targeting MOFs toward mitochondria represents a valuable strategy for the development of new drug delivery systems.

Multivariate Modulation of the Zr MOF UiO-66 for Defect-Controlled Combination Anticancer Drug Delivery.

Metal-organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO-66 by defect-loading. The drugs are added to one-pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination to the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF-7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis.

Synthesis and characterisation of a mesocyclic tripodal triamine ligand.

Meso- and macrocyclic polydentate amine ligands have been widely explored in oxidation catalysis and for the stabilization of unstable metal-superoxide, -peroxide, and -oxo intermediates. Herein we report on the design and synthesis of a novel mesocyclic, tripodal, triamine ligand that we believe will be an excellent addition to this field. We explored a number of synthetic procedures towards the mesocyclic asymmetric tetraalkylated ligand 1. We expect that 1 will bind metals in a facially capping manner, yielding complexes that display pseudo-tetrahedral geometry, potentially providing access to unprecedented late transition metal-oxo complexes (metal = Co, Ni, Cu). We describe the preparation of a library of mesocyclic polyamine synthons (8, 16, 17, 18, 19) that are precursors in the synthesis of 1. These synthons will be used to tailor the electronic properties of metal complexes of 1 and derivatives thereof. The X-ray crystal structures of 19 and mono- and di-protonated forms of 1b show that the triamine crystalises in a boat­chair conformation which is undesirable for metal coordination. However, solution (1)H NMR studies show that in solution both 19 and the tetraalkylated derivative 1b are remarkably flexible. 1b reacted with [CuI(NCCH3)4](OTf) yielding a 1:1 copper(I) complex [CuI(NCCH3)(1b)](+).

Structure-Function Relationship between Frequency-Doubling Technology Perimetry and Optical Coherence Tomography in Glaucoma.

Purpose: To assess the relationship between the retinal nerve fibre layer (RNFL) thickness and the frequency-doubling technology perimetry (FDT) outcome. Methods: Sixty-two healthy individuals and 72 glaucoma patients were prospectively selected. All participants underwent a reliable FDT and optical coherence tomography (OCT). Pearson correlations were calculated between the unlogged threshold values of FDT and RNFL thicknesses measured by OCT. Results: Mild to moderate correlations were found between a few points from FDT and RNFL thicknesses in the vertical axis. The nasal superior area of FDT and the RNFL thickness at the 7-o'clock position had the strongest correlation (0.434, p < 0.001). Conclusions: The poor agreement between FDT and OCT parameters suggests that both instruments assess different characteristics of glaucomatous optic neuropathy. The map obtained validates previously reported clinical findings and contributes to a better understanding of the structure-function relationship in glaucoma. © 2014 S. Karger AG, Basel.

Dating archaeological copper/bronze artifacts by using the voltammetry of microparticles.

A method for dating copper/bronze archaeological objects aged in atmospheric environments is proposed based on the specific signals for cuprite and tenorite corrosion products measured through the voltammtry of microparticles method. The tenorite/cuprite ratio increased with the corrosion time and fitted to a potential law that yielded a calibration curve usable for dating purposes.

Tuning the electronic properties of Zr UiO-66 through defect-functionalised multivariate modulation.

The multivariate modulation of Metal-Organic Frameworks is presented as a valuable tool to introduce multiple functional units into UiO-66 while increasing its porosity. This manuscript encloses a comprehensive study using p-functionalised benzoate -NO2, -SO3 and -SH modulators, rationalizing the defects introduced and their impact on properties.

Association of microbiological factors with mortality in Escherichia coli bacteraemia presenting with sepsis/septic shock: a prospective cohort study.

OBJECTIVES: This study aimed to determine the association of Escherichia coli microbiological factors with 30-day mortality in patients with bloodstream infection (BSI) presenting with a dysregulated response to infection (i.e. sepsis or septic shock). METHODS: Whole-genome sequencing was performed on 224 E coli isolates of patients with sepsis/septic shock, from 22 Spanish hospitals. Phylogroup, sequence type, virulence, antibiotic resistance, and pathogenicity islands were assessed. A multivariable model for 30-day mortality including clinical and epidemiological variables was built, to which microbiological variables were hierarchically added. The predictive capacity of the models was estimated by the area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals (CI). RESULTS: Mortality at day 30 was 31% (69 patients). The clinical model for mortality included (adjusted OR; 95% CI) age (1.04; 1.02-1.07), Charlson index ≥3 (1.78; 0.95-3.32), urinary BSI source (0.30; 0.16-0.57), and active empirical treatment (0.36; 0.11-1.14) with an AUROC of 0.73 (95% CI, 0.67-0.80). Addition of microbiological factors selected clone ST95 (3.64; 0.94-14.04), eilA gene (2.62; 1.14-6.02), and astA gene (2.39; 0.87-6.59) as associated with mortality, with an AUROC of 0.76 (0.69-0.82). DISCUSSION: Despite having a modest overall contribution, some microbiological factors were associated with increased odds of death and deserve to be studied as potential therapeutic or preventive targets.

Whole-genome characterisation of Escherichia coli isolates from patients with bacteraemia presenting with sepsis or septic shock in Spain: a multicentre cross-sectional study.

BACKGROUND: Escherichia coli is the most frequent cause of bloodstream infections (BSIs). About one-third of patients with BSIs due to E coli develop sepsis or shock. The objective of this study is to characterise the microbiological features of E coli blood isolates causing sepsis or septic shock to provide exploratory information for future diagnostic, preventive, or therapeutic interventions. METHODS: E coli blood isolates from a multicentre cross-sectional study of patients older than 14 years presenting with sepsis or septic shock (according to the Third International Consensus Definitions for Sepsis and Septic Shock criteria) from hospitals in Spain between Oct 4, 2016, and Oct 15, 2017, were studied by whole-genome sequencing. Phylogroups, sequence types (STs), serotype, FimH types, antimicrobial resistance (AMR) genes, pathogenicity islands, and virulence factors were identified. Susceptibility testing was performed by broth microdilution. The main outcome of this study was the characterisation of the E coli blood isolates in terms of population structure by phylogroups, groups (group 1: phylogroups B2, F, and G; group 2: A, B1, and C; group 3: D), and STs and distribution by geographical location and bloodstream infection source. Other outcomes were virulence score and prevalence of virulence-associated genes, pathogenicity islands, AMR, and AMR-associated genes. Frequencies were compared using χ² or Fisher's exact tests, and continuous variables using the Mann-Whitney test, with Bonferroni correction for multiple comparisons. FINDINGS: We analysed 224 isolates: 140 isolates (63%) were included in phylogenetic group 1, 52 (23%) in group 2, and 32 (14%) in group 3. 85 STs were identified, with four comprising 44% (n=98) of the isolates: ST131 (38 [17%]), ST73 (25 [11%]), ST69 (23 [10%]), and ST95 (12 [5%]). No significant differences in phylogroup or ST distribution were found according to geographical areas or source of bloodstream infection, except for ST95, which was more frequent in urinary tract infections than in other sources (11 [9%] of 116 vs 1 [1%] of 108, p=0·0045). Median virulence score was higher in group 1 (median 25·0 [IQR 20·5-29·0) than in group 2 (median 14·5 [9·0-20·0]; p<0·0001) and group 3 (median 21 [16·5-23·0]; p<0·0001); prevalence of several pathogenicity islands was higher in group 1. No significant differences were found between phylogenetic groups in proportions of resistance to antibiotics. ST73 had higher median virulence score (32 [IQR 29-35]) than the other predominant clones (median range 21-28). Some virulence genes and pathogenicity islands were significantly associated with each ST. ST131 isolates had higher prevalence of AMR and a higher proportion of AMR genes, notably blaCTX-M-15 and blaOXA-1. INTERPRETATION: In this exploratory study, the population structure of E coli causing sepsis or shock was similar to previous studies that included all bacteraemic isolates. Virulence genes, pathogenicity islands, and AMR genes were not randomly distributed among phylogroups or STs. These results provide a comprehensive characterisation of invasive E coli isolates causing severe response syndrome. Future studies are required to determine the contribution of these microbiological factors to severe clinical presentation and worse outcomes in patients with E coli bloodstream infection. FUNDING: Instituto de Salud Carlos III.

Hierarchical mesoporous NanoMUV-2 for the selective delivery of macromolecular drugs.

Although Metal-organic frameworks (MOFs) have received attention as drug delivery systems, their application in the delivery of macromolecules is limited by their pore size and opening. Herein, we present the synthesis of nanostructured MUV-2, a hierarchical mesoporous iron-based MOF that can store high payloads of the macromolecular drug paclitaxel (ca. 23% w/w), increasing its selectivity towards HeLa cancer cells over HEK non-cancerous cells. Moreover, this NanoMUV-2 permits full degradation under simulated physiological conditions while maintaining biocompatibility, and is amenable to specific surface modifications that increase its cell permeation, efficient cytosol delivery and cancer-targeting effect, further intensifying the cancer selectivity of paclitaxel.

Imparting structural robustness of metal-organic cages based on oxo-dimolybdenum clusters.

A family of robust and stable molybdenum-based metal-organic cages have been obtained based on the [Mo2O2(µ2-O)2]2+ secondary building unit. The resulting cages are decorated with different pyrdine derivatives that impart structural stability, resulting in the structural elucidation of the activated cage with single-crystal diffraction. The chemical robustness of the cage is also demonstrated by the post-synthetic modification of the cage, which allows the exchange of the pyridine derivatives without rupture of the cage.

Ultramicroporous iron-isonicotinate MOFs combining size-exclusion kinetics and thermodynamics for efficient CO2/N2 gas separation.

Two ultramicroporous 2D and 3D iron-based Metal-Organic Frameworks (MOFs) have been obtained by solvothermal synthesis using different ratios and concentrations of precursors. Their reduced pore space decorated with pendant pyridine from tangling isonicotinic ligands enables the combination of size-exclusion kinetic gas separation, due to their small pores, with thermodynamic separation, resulting from the interaction of the linker with CO2 molecules. This combined separation results in efficient materials for dynamic breakthrough gas separation with virtually infinite CO2/N2 selectivity in a wide operando range and with complete renewability at room temperature and ambient pressure.

MOF nanoparticles as heterogeneous catalysts for direct amide bond formations.

The influence of composition and textural characteristics of a family of ultra-small isoreticular UiO-type metal-organic frameworks (MOFs) with different functionalized and extended linkers on their catalytic performance is evaluated. Two direct amide bond formations across four different substrates (benzylamine + phenylacetic acid and aniline + formic acid) are employed as proof-of-concept reactions to test the activity of the Zr-MOF nanoparticles. The reaction rates of amide bond formation are evaluated against physico-chemical properties such as crystallinity, porosity, particle size or linker functionality, alongside the Lewis acid and hydrophobic properties of the MOFs, in order to gain insights into the catalytic mechanism and optimal properties for its enhancement.

Tuning the Photocatalytic Activity of Ti-Based Metal-Organic Frameworks through Modulator Defect-Engineered Functionalization.

Defect engineering is a valuable tool to tune the photocatalytic activity of metal-organic frameworks (MOFs). Inducing defects through the attachment of functionalized modulators can introduce cooperative units that can tune the bandgap of the material and enhance their chemical, thermal, and photostabilities among other properties. However, the majority of defect engineering studies for photocatalytic applications are limited to Zr-based MOFs, and there is still a lack of interrelation between synthetic variables, the resultant MOF properties, and their effect on their photocatalytic performance. We report a comprehensive study on the defect engineering of the titanium heterometallic MOF MUV-10 by fluoro- and hydroxy-isophthalic acid (Iso) modulators, rationalizing the effect of the materials' properties on their photocatalytic activity for hydrogen production. The Iso-OH modified MOFs present a volcano-type profile with a 2.3-fold increase in comparison to the pristine materials, whereas the Iso-F modified samples have a gradual increase with up to a 4.2-fold enhancement. It has been demonstrated that ∼9% of Iso-OH modulator incorporation produces ∼40% defects, inducing band gap reduction and longer excited states lifetime. Similar defect percentages have been generated upon near 40% Iso-F modulator incorporation; however, negligible band gap changes and shorter excited states lifetimes were determined. The higher photocatalytic activity in Iso-F modulator derived MOF has been attributed to the effect of the divergent defect-compensation modes on the materials' photostability and to the increase in the external surface area upon introduction of Iso-F modulator.

Controlling the molecular diffusion in MOFs with the acidity of monocarboxylate modulators.

The catalytic performance of metal-organic frameworks (MOFs) is related to their physicochemical properties, such as particle size, defect chemistry and porosity, which can be potentially controlled by coordination modulation. By combining PXRD, 1HNMR, FT-IR, and N2 uptake measurements we have gained insights into the control of different types of defects (missing linker or missing cluster consequence of the spatial distribution of missing linkers, and a combination of both) by the type of modulator employed. We show that the molar percent of defects, either as missing linkers or as a part of missing cluster defects, is related to the acidity of a modulator and its subsequent incorporation into the UiO-66 structure. Modulators with strong acidity and small size result in a considerable defect induction that causes an increase in the external surface area and mesopore volume, which is beneficial for the ring-opening of epoxides with amines, using UiO-66 defect-modulated MOFs as heterogeneous catalysts.

Linker depletion for missing cluster defects in non-UiO metal-organic frameworks.

Defect engineering is a valuable tool to tune the properties of metal-organic frameworks. However, defect chemistry remains still predominantly limited to UiO-type MOFs. We describe the preferential formation of missing cluster defects in heterometallic titanium-organic frameworks of the MUV-10 family when synthesised in sub-stoichiometric linker conditions. Our results show the value of integrating experimental work, computational modelling and thorough characterization in rationalizing the impact of defects over the porosity and structure of this family of materials. Correlation of experiment with computational models reveals the dominance of missing cluster vacancies in the pore size distribution of defective MUV-10. These same models were used to investigate the correlation of defects by synchrotron X-ray diffraction. The diffraction at low reflection angles is dominated by diffuse scattering that is indicative of short-range order and cannot be indexed to the defective structural models generated. In addition to the low atomic scattering factor of titanium, these results confirm the need for high-resolution electron microscopy methods for modelling nanoscale disorder in titanium MOFs.

The excellent biocompatibility and negligible immune response of the titanium heterometallic MOF MUV-10.

The Ti-Ca heterometallic MOF MUV-10 exhibits good dispersibility in phosphate buffer and low phosphate-induced degradation in comparison to other MOF systems. It induces no cytotoxicity towards cells of the immune system and no inmune response, making it an attractive candidate for biomedical applications and demonstrating its safe use for other applications.

Presence of Arsenic in Potential Sources of Drinking Water Supply Located in a Mineralized and Mined Area of the Sierra Madre Oriental in Mexico.

Mine wastes from the La Aurora mine in the state of Guanajuato were generated by the flotation process and placed in four tailing dumps on the local stream while the plant operated. Given that these wastes contain toxic elements, it is important to establish their impact on the quality of several surrounding natural sources of water that are considered potential drinking water supplies. This study identified four water source types, in which the contents of arsenic (As), mercury (Hg), and thallium (Tl) were exceeded, according to international guideline values for drinking water quality. The first type of aqueous sample corresponded to leachates produced by rainwater infiltration in tailings and water-mineral waste interactions. The second type corresponded to surface water along the Xichú and La Laja Streams, and the third and fourth types involved two groundwater well samples and spring samples, respectively. The Chiquito Stream was used as a reference area that had not been impacted by the mine wastes. The isotopic signatures associated with δ34Ssulfate and δ18Osulfate compositions from the El Ojo de Agua spring are similar to those of the Santa María River and are different from those of the mine waste leachates. This study shows evidence of the presence of As in the El Ojo de Agua spring, which results from dissolution of secondary mineral phases that were produced by alteration of the mine wastes, which then migrated along the Xichú Stream system until reaching the spring. These As-bearing fine particles are prone to dissolution when in contact with this water source. Principal component analysis revealed that the observed As, Tl, and Hg can be attributed to weathering of the mine wastes. However, the results suggest that a natural contribution of these elements could be associated with rainwater-igneous rock interactions.

Effect of modulator connectivity on promoting defectivity in titanium-organic frameworks.

The recognition of defect chemistry as a true synthetic tool for targeted creation of defects and controllable performance remains limited by the pool of frameworks explored. The value of defect engineering in controlling the properties of defective frameworks has been beautifully exemplified and largely demonstrated with UiO-type materials based on Zr(iv) nodes. However, titanium-organic frameworks remain largely unexplored in this context arguably due to the complex chemistry in solution of Ti(iv) and the difficulties in growing crystalline solids. We report a systematic study on the ability of mono- and dicarboxylic modulators (benzoic and isophthalic acid) to promote defect creation in the heterometallic Ti-MOF of the MUV-10 family. Our results indicate that both acids behave as capping modulators at high concentrations, but isophthalic acid is a more efficient defect promoter, yielding defective phases with nearly 40% of missing linkers. Our computational results suggest that this difference cannot be solely ascribed to relative changes in acidity but to the ability of this bidentate linker in compensating the structural distortion and energy penalty imposed by breaking the connectivity of the underlying framework.

Controlled Transdermal Release of Antioxidant Ferulate by a Porous Sc(III) MOF.

The Sc(III) MOF-type MFM-300(Sc) is demonstrated in this study to be stable under physiological conditions (PBS), biocompatible (to human skin cells), and an efficient drug carrier for the long-term controlled release (through human skin) of antioxidant ferulate. MFM-300(Sc) also preserves the antioxidant pharmacological effects of ferulate while enhancing the bio-preservation of dermal skin fibroblasts, during the delivery process. These discoveries pave the way toward the extended use of Sc(III)-based MOFs as drug delivery systems (DDSs).

Antiphospholipid antibodies may impair factor XIIa-dependent activation of fibrinolysis in pregnancy: in vitro evidence with human endothelial cells in culture and monoclonal anticardiolipin antibodies.

OBJECTIVE: The purpose of this study was to analyze the in vitro activation of the contact complex with the use of human umbilical vein endothelial cells (HUVEC) in culture and monoclonal anticardiolipin antibodies (MaCL). STUDY DESIGN: Cultured HUVECs were incubated with pooled plasma from third-trimester pregnant women with the addition (20 mg/mL) of MaCL with anti-beta-2 glycoprotein I activity that was obtained from patients with antiphospholipid syndrome (APS), MaCL from an individual without APS, or from a control patient with immunoglobulin M without aCL activity. Supernatants were evaluated. Activated factors XII and VII, prothrombin-fragment 1 + 2, urokinase-type plasminogen activator (UPA), and differentiating 2 chain UPA were determined. RESULTS: In the cultured HUVEC supernatants, the addition of MaCL increased activated factor VII and prothrombin-fragment 1 + 2, did not modify UPA, and decreased activated factor XII and differentiating 2 chain UPA, in comparison with samples with control immunoglobulin M added. The MaCL without APS activity did not change any parameter that was evaluated. CONCLUSION: MaCL with anti-beta-2 activity that was obtained from patients with APS may interfere in the activation of the contact complex during pregnancy.