Treatment of intralocular diseases with poly(ortho ester)‐based drug delivery systems

A poly(ortho ester) (POE) has been investigated as a carrier for controlled delivery in intraocular therapy. The intraocular biocompatibility of POE was assessed in the rabbit after intravitreal as well as suprachoroidal injections. In both cases, the injection was feasible and reproducible, and the tolerance of POE was good, with no clinical or cellular signs of inflammation. The polymer degraded slowly within 2 to 3 weeks, with total bioresorption. POE allowed to sustain the release of an antifibroblastic agent in a model of glaucoma filtering surgery in the rabbit. A formulation based on POE and 5‐fluorouracil was administered to prevent the failure of the surgery. This POE formulation was effective in inhibiting the fibrotic response, allowing a local and controlled release of a small amount of the antiproliferative drug, while reducing its toxicity. Based on these results, POE appears to be a promising carrier for sustained drug delivery in treatment of intraocular affections.     

Fungicidal Activity of Recombinant Javanicin against Cryptococcus neoformans Is Associated with Intracellular Target(s) Involved in Carbohydrate and Energy Metabolic Processes

The occurrence of Cryptococcus neoformans, the human fungal pathogen that primarily infects immunocompromised individuals, has been progressing at an alarming rate. The increased incidence of infection of C. neoformans with antifungal drugs resistance has become a global concern. Potential antifungal agents with extremely low toxicity are urgently needed. Herein, the biological activities of recombinant javanicin (r-javanicin) against C. neoformans were evaluated. A time-killing assay was performed and both concentration- and time-dependent antifungal activity of r-javanicin were indicated. The inhibitory effect of the peptide was initially observed at 4 h post-treatment and ultimately eradicated within 36 to 48 h. Fungal outer surface alteration was characterized by the scanning electron microscope (SEM) whereas a negligible change with slight shrinkage of external morphology was observed in r-javanicin treated cells. Confocal laser scanning microscopic analysis implied that the target(s) of r-javanicin is conceivably resided in the cell thereby allowing the peptide to penetrate across the membrane and accumulate throughout the fungal body. Finally, cryptococcal cells coped with r-javanicin were preliminarily investigated using label-free mass spectrometry-based proteomics. Combined with microscopic and proteomics analysis, it was clearly elucidated the peptide localized in the intracellular compartment where carbohydrate metabolism and energy production associated with glycolysis pathway and mitochondrial respiration, respectively, were principally interfered. Overall, r-javanicin would be an alternative candidate for further development of antifungal agents.     

Porphyrin-Based Thin-Film Molecular Materials with Highly Adjustable Nanoscale Porosity and Permeability Characteristics

Mesoporous thin films based on neutral, porphyrin-bridged, tetrarhenium “square” compounds (metallacycles) display permeability to molecules smaller than the dimensions of an individual square cavity, but blocking behavior toward larger species (see schematic representation). The characteristic permeant size cutoff can be systematically and predictably manipulated by decorating the walls of the porphyrin square with axially bound, mono-, bi-, and tetradentate ligands.     

Difference in thermal behaviour between 1- and 2-alkyl-5-(methoxycarbonyldiazomethyl)tetrazoles

In continuation of previous work, isomeric diazoester-substituted alkyltetrazoles 5 and 6 have been synthesized by the diazo-transfer method and studied in thermolysis reactions. Whereas the N-1 alkyl derivatives 5 give norcaradienes 7 in benzene solution and imidazotetrazoles 12 in acetonitrile, the more thermostable N-2 alkyl isomers 6 yield fluxional norcaradiene-cycloheptatriene systems, 10 – 11 , and ox-azoles 13.     

Synthesis of some 5,6,7,8-tetrahydro-4-cinnolone derivatives and 1-methyl-3-arylacetyl-4,5,6,7-tetrahydroindazoles

2-Arylidene-3-oxo-2,3,4,5,6,7-hexahydrobenzo[b]furans 2 react with hydrazine hydrate to afford 5,6,7,8-tetrahydro-4-cinnolones. By methylation, these compounds gave the corresponding N-1 and N-2 methyl derivatives. The mesoionic compounds are obtained, accompanied by 3-arylacetyl-4,5,6,7-tetrahydroindazoles upon reaction of 2 with methylhydrazine.     

Inclusion complexes of a nucleotide analogue with hydroxypropyl-beta-cyclodextrin

Bis(tbutyl-S-acyl-2-thioethyl)-AraCMP (UA911) is a mononucleotide prodrug developed to overcome some of the cellular resistance to cytotoxic deoxynucleosides analogues. Its use for in vivo studies is limited due to its poor solubility in water. Thus, 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) was proposed to solubilize UA911 in water, in order to obtain concentrations needed for in vivo experiments. A molar ratio of HP-β-CD: UA911 of 3:1 was sufficient to obtain complete solubilization of the prodrug. The corresponding inclusion complex was characterized by differential scanning calorimetry and ¹H NMR spectroscopy study provided a definitive proof of the formation of the inclusion complex. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells, and was evaluated in vivo. HP-β-CD is therefore suitable for the preparation of adequate solutions for the study of the antitumoral activity of nucleotide prodrugs such as UA911.     

Matisse to Picasso: a compositional study of modern bronze sculptures

Inductively coupled plasma-optical emission spectroscopy (ICP-OES) was used to determine the bulk metal elemental composition of 62 modern bronze sculptures cast in Paris in the first half of the twentieth century from the collections of The Art Institute of Chicago and the Philadelphia Museum of Art. As a result, a comprehensive survey of the alloy composition of the sculptures of many prominent European artists of the early twentieth century is presented here for the first time. The sculptures in this study consist of predominantly copper with two main alloying elements (zinc and tin). By plotting the concentrations of these two elements (zinc and tin) against each other for all the sculptures studied, three clusters of data become apparent: (A) high-zinc brass; (B) low-zinc brass; (C) tin bronze. These clusters correlate to specific foundries, which used specific casting methods (sand or lost wax) that were influenced by individual preferences and technical skills of the foundry masters. For instance, the high-zinc brass alloys (with the highest levels of tin and zinc and the lowest melting temperature) correspond to most of the Picasso sculptures, correlate with the Valsuani foundry, and are associated with the most recent sculptures (post-WWII) and with the lost-wax casting method. By expanding the ICP-OES database of objects studied, these material correlations may become useful for identifying, dating, or possibly even authenticating other bronzes that do not bear foundry marks. Figure   Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Dendrimer-tuned formation of fluorescent organic microcrystals. Influence of dye hydrophobicity and dendrimer charge

The reprecipitation method is a simple and useful way to prepare microcrystals through a solvent exchange process. It was applied to three fluorescent dyes of the 4-amino-7-nitrobenz-2-oxa-1,3-diazole series. Compounds 1, 2, and 3 differ by the length of the alkyl chain, which comprises 8, 12, and 18 carbon atoms, respectively. The reprecipitation process was first studied in water, in the absence of additives. The kinetics was monitored by UV/vis absorption spectroscopy. The size and shape of the microparticles were analyzed by fluorescence microscopy and transmission electron microscopy. Dyes 1 and 2 lead to microcrystals, the whole process taking much more time for 2 than for 1. The long-chained dye 3 only gave stable aggregates. Therefore, it appears that the hydrophobicity of the organic dye markedly influenced the reprecipitation process. The latter was then studied in the presence of additives. Poly(amidoamine) dendrimers, terminated by 64 carboxylate or amino groups were placed in the reprecipitation medium. They had little effect upon the formation of aggregates for dye 3. In contrast, they drastically accelerated the reprecipitation of 1 and 2 and tuned the size and shape of the microcrystals. Platelets and spindles were thus obtained by varying the nature of the dendrimer, and their optical properties were briefly investigated.     

[3+2]- Versus [4+2]-cycloaddition reactions of 3-methylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles with N-substituted maleimides involving pyrrolidine-derived azomethine ylides

3-Methylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles do not enter into [4+2]-cycloaddition reactions with maleimides to form the expected pyrrolo-pyridazines. Instead the formation of novel pyrrolo-pyridazines of type 4 takes place via a formal [3+2]-cycloaddition of initially formed pyrrolidine-derived azomethine ylides 7. The mechanism leading to the final product is discussed.