Exploring the Role of Metal in the Biointeraction of Metallacarboranes with C. elegans Embryos.

Cobaltabis(dicarbollides), ferrabis(dicarbollide), and their halogenated derivatives are the most studied metallacarboranes with great medical potential. These versatile compounds and their iodinated derivatives can be used in chemotherapy, radiotherapy, particle therapy, and bioimaging when isotopes are used. These metallacarboranes have been evaluated in vitro and recently in vivo with complex animal models. Lately, these studies have been complemented using the invertebrate Caenorhabditis elegans (C. elegans), a nematode largely used in toxicology. When evaluated at the L4 stage, cobaltabis(dicarbollides), ([o-COSAN]- and [8,8'-I2 -o-COSAN]- ), exhibited a higher mean lethal dose (LD50 ) than ferrabis(dicarbollides) ([o-FESAN]- and [8,8'-I2 -o-FESAN]- ). In this work, we used the C. elegans embryos since they are a complex biological barrier with concentric layers of polysaccharides and proteins that protect them from the environment. We assessed if the metal atom changes their biointeraction with the C. elegans embryos. First, we assessed the effects on embryo development for metallacarboranes and their di-iodinated derivatives. We observed changes in color and in their surface structure. An exhaustive physicochemical characterization was performed to understand better this interaction, revealing a stronger interaction of ferrabis(dicarbollide) compounds with C. elegans embryos than the cobaltabis(dicarbollide) molecules. Unveiling the biological interaction of these compounds is of great interest for their future biomedical applications.

Towards the Application of Purely Inorganic Icosahedral Boron Clusters in Emerging Nanomedicine.

Traditionally, drugs were obtained by extraction from medicinal plants, but more recently also by organic synthesis. Today, medicinal chemistry continues to focus on organic compounds and the majority of commercially available drugs are organic molecules, which can incorporate nitrogen, oxygen, and halogens, as well as carbon and hydrogen. Aromatic organic compounds that play important roles in biochemistry find numerous applications ranging from drug delivery to nanotechnology or biomarkers. We achieved a major accomplishment by demonstrating experimentally/theoretically that boranes, carboranes, as well as metallabis(dicarbollides), exhibit global 3D aromaticity. Based on the stability-aromaticity relationship, as well as on the progress made in the synthesis of derivatized clusters, we have opened up new applications of boron icosahedral clusters as key components in the field of novel healthcare materials. In this brief review, we present the results obtained at the Laboratory of Inorganic Materials and Catalysis (LMI) of the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) with icosahedral boron clusters. These 3D geometric shape clusters, the semi-metallic nature of boron and the presence of exo-cluster hydrogen atoms that can interact with biomolecules through non-covalent hydrogen and dihydrogen bonds, play a key role in endowing these compounds with unique properties in largely unexplored (bio)materials.

Aromaticity and Extrusion of Benzenoids Linked to [o-COSAN]- : Clar Has the Answer.

Benzene and pyrene can be synthetically linked to [o-COSAN]- keeping their aromaticity. In contrast, naphthalene and anthracene are extruded in the same reaction. We have proven that extrusion is only favorable if the number of Clar's π-sextets remains constant. Thus, Clar has the answer to whether an attached polycyclic aromatic hydrocarbon to [o-COSAN]- is extruded or not.

Metallacarborane Derivatives Effective against Pseudomonas aeruginosa and Yersinia enterocolitica.

Pseudomonas aeruginosa is an opportunistic human pathogen that has become a nosocomial health problem worldwide. The pathogen has multiple drug removal and virulence secretion systems, is resistant to many antibiotics, and there is no commercial vaccine against it. Yersinia pestis is a zoonotic pathogen that is on the Select Agents list. The bacterium is the deadliest pathogen known to humans and antibiotic-resistant strains are appearing naturally. There is no commercial vaccine against the pathogen, either. In the current work, novel compounds based on metallacarborane cage were studied on strains of Pseudomonas aeruginosa and a Yersinia pestis substitute, Yersinia enterocolitica. The representative compounds had IC50 values below 10 µM against Y. enterocolitica and values of 20-50 µM against P. aeruginosa. Artificial generation of compound-resistant Y. enterocolitica suggested a common mechanism for drug resistance, the first reported in the literature, and suggested N-linked metallacarboranes as impervious to cellular mechanisms of resistance generation. SEM analysis of the compound-resistant strains showed that the compounds had a predominantly bacteriostatic effect and blocked bacterial cell division in Y. enterocolitica. The compounds could be a starting point towards novel anti-Yersinia drugs and the strategy presented here proposes a mechanism to bypass any future drug resistance in bacteria.

Atomistic Simulations of COSAN: Amphiphiles without a Head-and-Tail Design Display "Head and Tail" Surfactant Behavior.

Cobaltabisdicarbollide (COSAN) anions have an unexpectedly rich self-assembly behavior, which can lead to vesicles and micelles without having a classical surfactant molecular architecture. This was rationalized by the introduction of new terminology and novel driving forces. A key aspect in the interpretation of COSAN behavior is the assumption that the most stable form of these ions is the transoid rotamer, which lacks a "hydrophilic head" and a "hydrophobic tail". Using implicit solvent DFT calculations and MD simulations we show that in water, 1) the cisoid rotamer is the most stable form of COSAN and 2) this cisoid rotamer has a well-defined hydrophilic polar region ("head") and a hydrophobic apolar region ("tail"). In addition, our simulations show that the properties of this rotamer in water (interfacial affinity, micellization) match those expected for a classical surfactant. Therefore, we conclude that the experimental results for the COSAN ions can now be understood in terms of its amphiphilic molecular architecture.

Four Covariance Structure Models for Canonical Correlation Analysis: A COSAN Modeling Approach.

The mathematical connection between canonical correlation analysis (CCA) and covariance structure analysis was first discussed through the Multiple Indicators and Multiple Causes (MIMIC) approach. However, the MIMIC approach has several technical and practical challenges. To address these challenges, a comprehensive COSAN modeling approach is proposed. Specifically, we define four COSAN-CCA models to correspond with four possible combinations of the data to be analyzed and the unique parameters to be estimated. In terms of the data, one can analyze either the unstandardized or standardized variables. In terms of the unique parameters, one can estimate either the weights or loadings. Besides the unique parameters of each COSAN-CCA model, all four COSAN-CCA models also estimate the canonical correlations as their common parameters. Taken together, the four COSAN-CCA models provide the correct point estimates and standard error estimates for all commonly used CCA parameters. Two numeric examples are used to compare the standard error estimates obtained from the MIMIC approach and the COSAN modeling approach. Moreover, the standard error estimates from the COSAN modeling approach are validated by a simulation study and the asymptotic theory. Finally, software implementation and future extensions are discussed.

Aqueous solubilization of hydrophobic compounds by inorganic nano-ions: An unconventional mechanism.

HYPOTHESIS: Solubilization of hydrophobic compounds in water is commonly performed by using organic solubilizers such as hydrotropes, surfactants, co-solvents, and macrocycles to form host-guest complexes. 3,3'-commo-bis[closo-1,2-dicarba-3-cobaltadodecaborane] derivatives (COSANs) are fully inorganic and non-amphiphilic ionic boron clusters with nanometric size (nano-ions) showing superchaotropic properties as they strongly bind to neutral organic molecules. Therefore, we expect COSANs to act as solubilizers of sparingly water-soluble molecules, but with a mechanism different from all other organic solubilizers known so far. EXPERIMENTS: The aqueous solubilization efficiency of COSANs towards butanol was evaluated by determining phase diagrams and comparing them to classical solubilizers. Nanostructuration of the mixture was studied using UV spectroscopy, small-angle X-ray, and neutron scattering with contrast variation. FINDINGS: COSANs act as efficient aqueous solubilizers of medium-chain alcohols (0.6 < log P < 1.5). Unlike surfactants, COSAN is an efficient solubilizer in its monomeric state, at concentrations well below its critical aggregation concentration. Solubilization by COSAN takes place with a bi-dimensional anisotropic growth of COSAN/butanol co-assemblies, whereas solubilization by surfactant occurs via an isotropic swelling of micelles. Appealingly, COSANs/2-butanol co-assemblies efficiently solubilize more hydrophobic compounds with log P values up to around 6, offering new opportunities in many applied fields.

In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection.

Carboranes have emerged as one of the most promising boron agents in boron neutron capture therapy (BNCT). In this context, in vivo studies are particularly relevant, since they provide qualitative and quantitative information about the biodistribution of these molecules, which is of the utmost importance to determine the efficacy of BNCT, defining their localization and (bio)accumulation, as well as their pharmacokinetics and pharmacodynamics. First, we gathered a detailed list of the carboranes used for in vivo studies, considering the synthesis of carborane derivatives or the use of delivery system such as liposomes, micelles and nanoparticles. Then, the formulation employed and the cancer model used in each of these studies were identified. Finally, we examined the analytical aspects concerning carborane detection, identifying the main methodologies applied in the literature for ex vivo and in vivo analysis. The present work aims to identify the current strengths and weakness of the use of carboranes in BNCT, establishing the bottlenecks and the best strategies for future applications.

Selective Antibody-Free Sensing Membranes for Picogram Tetracycline Detection.

As an antibody-free sensing membrane for the detection of the antibiotic tetracycline (TC), a liquid PVC membrane doped with the ion-pair tetracycline/θ-shaped anion [3,3'-Co(1,2-C2B9H11)2]- ([o-COSAN]-) was formulated and deposited on a SWCNT modified gold microelectrode. The chosen transduction technique was electrochemical impedance spectroscopy (EIS). The PVC membrane was composed of: the tetracycline/[o-COSAN]- ion-pair, a plasticizer. A detection limit of 0.3 pg/L was obtained with this membrane, using bis(2-ethylhexyl) sebacate as a plasticizer. The sensitivity of detection of tetracycline was five times higher than that of oxytetracycline and of terramycin, and 22 times higher than that of demeclocycline. A shelf-life of the prepared sensor was more than six months and was used for detection in spiked honey samples. These results open the way to having continuous monitoring sensors with a high detection capacity, are easy to clean, avoid the use of antibodies, and produce a direct measurement.

Cobaltabis(dicarbollide) ([o-COSAN]-) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma.

PURPOSE: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8'-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. METHODS: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. RESULTS: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8'-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. CONCLUSIONS: These small molecules, particularly [8,8'-I2-o-COSAN]-, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma.