Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles

Excessive apoptotic cell death is at the origin of several pathologies, such as degenerative disorders, stroke or ischemia‐reperfusion damage. In this context, strategies to improve inhibition of apoptosis and other types of cell death are of interest and may represent a pharmacological opportunity for the treatment of cell‐death‐related disorders. In this scenario new peptide‐containing delivery systems (solids S₁ ‐ P₁ and S₁ ‐ P₂ ) are described based on mesoporous silica nanoparticles (MSNs) loaded with a dye and capped with the KKGDEVDKKARDEVDK ( P₁ ) peptide that contains two repeats of the DEVD target sequence that are selectively hydrolyzed by caspase 3 ( C3 ). This enzyme plays a central role in the execution‐phase of apoptosis. HeLa cells electroporated with S₁ – P₁ are able to deliver the cargo in the presence of staurosporin (STS), which induces apoptosis with the consequent activation of the cytoplasmic C3 enzyme. Moreover, the nanoparticles S₁ ‐ P₂ , containing both a cell‐penetrating TAT peptide and P₁ also entered in HeLa cells and delivered the cargo preferentially in cells treated with the apoptosis inducer cisplatin.     

Spatially Close Azo Dyes with Sub‐Nanosecond Switching Speeds and Exceptional Temporal Resolution

Photoswitchable bis‐azo dyes with an outstanding temporal resolution of 10¹⁵ times between the thermal relaxation rates of their two constituting photochromes are reported. Remarkably, the close spatial proximity of both azo photochromes in these molecular assemblies translates in an unprecedented 10³‐fold acceleration of the thermal isomerization rate of their faster azo unit compared to the one displayed by the isolated counterpart. Indeed, the relaxation time of the fast‐isomerizing platform of the herein reported bis‐azobenzenes is as low as 200 ps under ambient conditions. In the wake of these results, the bis‐azo dyes described herein are invaluable chromophores for the design of multifunctional light‐addressable materials in which simultaneous switching in two very different timescales might be essential.     

Direct X‐Ray Scattering Evidence for Metal–Metal Interactions in Solution at the Molecular Level

The study of the aggregation of small molecules in solution induced by metallophilic interactions has been traditionally performed by spectroscopic methods through identification of chemical changes in the system. Herein we demonstrate the use of SAXS (small‐angle X‐ray scattering) to identify structures in solution, taking advantage of the excellent scattering intensity of heavy metals which have undergone association by metallophilic interactions. An analysis of the close relationship between solid‐state and solution arrangements of a dynamic [Ag₂(bisNHC)₂]²⁺ (NHC=N‐heterocyclic carbene) system, and how they are complementary to each other, is reported.     

Gold(I)‐Assisted α‐Allylation of Enals and Enones with Alcohols

The intermolecular α‐allylation of enals and enones occurs by the condensation of variously substituted allenamides with allylic alcohols. Cooperative catalysis by [Au(ItBu)NTf₂] and AgNTf₂ enables the synthesis of a range of densely functionalized α‐allylated enals, enones, and acyl silanes in good yield under mild reaction conditions. DFT calculations support the role of an α‐gold(I) enal/enone as the active nucleophilic species.     

Physicochemical and Microbiological Stability of Two Oral Solutions of Methadone Hydrochloride 10 mg/mL

In this article, we studied physicochemical and microbiological stability and determined the beyond-use date of two oral solutions of methadone in three storage conditions. For this, two oral solutions of methadone (10 mg/mL) were prepared, with and without parabens, as preservatives. They were packed in amber glass vials kept unopened until the day of the test, and in a multi-dose umber glass bottle opened daily. They were stored at 5 ± 3 °C, 25 ± 2 °C and 40 ± 2 °C. pH, clarity, and organoleptic characteristics were obtained. A stability-indicating high-performance liquid chromatography method was used to determine methadone. Microbiological quality was studied and antimicrobial effectiveness testing was also determined following European Pharmacopoeia guidelines. Samples were analyzed at days 0, 7, 14, 21, 28, 42, 56, 70, and 91 in triplicate. After 91 days of storage, pH remained stable at about 6.5–7 in the two solutions, ensuring no risk of methadone precipitation. The organoleptic characteristics remained stable (colorless, odorless, and bitter taste). The absence of particles was confirmed. No differences were found with the use of preservatives. Methadone concentration remained within 95–105% in all samples. No microbial growth was observed. Hence, the two oral methadone solutions were physically and microbiologically stable at 5 ± 3 °C, 25 ± 2 °C, and 40 ± 2 °C for 91 days in closed and opened amber glass bottles.     

ATRP Enhances Structural Correlations In Polymerization-Induced Phase Separation**

Synthetic methods to control the structure of materials at sub-micron scales are typically based on the self-assembly of structural building blocks with precise size and morphology. On the other hand, many living systems can generate structure across a broad range of length scales in one step directly from macromolecules, using phase separation. Here, we introduce and control structure at the nano- and microscales through polymerization in the solid state, which has the unusual capability of both triggering and arresting phase separation. In particular, we show that atom transfer radical polymerization (ATRP) enables control of nucleation, growth, and stabilization of phase-separated poly-methylmethacrylate (PMMA) domains in a solid polystyrene (PS) matrix. ATRP yields durable nanostructures with low size dispersity and high degrees of structural correlations. Furthermore, we demonstrate that the length scale of these materials is controlled by the synthesis parameters.     

PIXE and EMP analyses of volcanites from Nea Kameni island (Aegean Sea,Greece)

The major and trace element compositions of several minerals and their surrounding groundmass in the volcanic rocks from the post-caldera Nea-Kameni island of the Santorini volcanic complex, Aegean Sea, have been determined, in-situ with particle-induced X-ray emission (PIXE) and wavelength dispersive X-ray analysis with an electron microprobe (EMP).The lavas are typically calc-alkaline dacites. All samples are porphyritic with a phenocryst mineralogy dominated by plagioclase, augite, hyperstene and Ti-magnetite. The phenocrysts range in size from 200 m to 2.5 mm.The PIXE and EMP analyses were done on sections polished with diamond paste. They were sufficiently thick ( 100 m) to stop the 2.7 MeV protons used for the analysis and yet thin enough for individual minerals to be seen with transmitted light. The specific minerals and groundmass areas to be analyzed had been selected and marked through conventional microscopic examination prior to analysis.Solid/liquid partition coefficients, which depend much less significantly on the method for determining the concentrations, were calculated from the element abundances in phenocrysts and corresponding groundmass.     

Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]⁶-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT₂R/AT₁R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2 , has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21.