Unprecedented J‐Aggregated Dyes in Pure Organic Solvents

The design and synthesis of the first organic dyes enabling spontaneous formation of stable J‐aggregates in common organic solvents without additives is described. The new dyes are O‐BODIPYs with a B‐spiranic 4,4‐diacyloxyl substitution pattern. Key to the effectiveness of the J‐aggregation process is the high conformational rigidity of the B‐spiranic molecular design as well as the orthogonal disposition of the B‐diacyloxyl substituent and the meso‐aryl group with respect to the mean plane of the boradiazaindacene. Atomistic simulations, both in vacuum and in a solvent cage, support the dynamics of the J‐aggregation process as well as its dependence on the alkylation pattern of the BODIPY chromophore. A detailed analysis of the photophysical and laser properties of the new dyes provides convincing evidence for the unambiguous assignment of these J‐aggregates and their dependence on the environmental conditions.     

Conveying a newly designed hydrophilic anti-human thymidylate synthase peptide to cisplatin resistant cancer cells: are pH-sensitive liposomes more effective than conventional ones?

Context: LR-peptide, a novel hydrophilic peptide synthetized and characterized in previous work, is able to reduce the multi-drug resistance response in cisplatin (cDPP) resistant cancer cells by inhibiting human thymidylate synthase (hTS) overexpressed in several tumors, including ovarian and colon-rectal cancers, but it is unable to enter the cells spontaneously.

Objective: The aim of this work was to design and characterize liposomal vesicles as drug delivery systems for the LR peptide, evaluating the possible benefits of the pH-responsive feature in improving intracellular delivery.

Materials and methods: For this purpose, conventional and pH-sensitive liposomes were formulated, compared regarding their physical-chemical properties (size, PDI, morphology, in vitro stability and drug release) and studied for in vitro cytotoxicity against a cDDP-resistant cancer cells.

Results and discussion: Results indicated that LR peptide was successfully encapsulated in both liposomal formulations but at short incubation time only LR loaded pH-sensitive liposomes showed cell inhibition activity while for long incubation time the two kinds of liposomes demonstrated the same efficacy.

Conclusions: Data provide evidence that acidic pH-triggered liposomal delivery is able to significantly reduce the time required by the systems to deliver the drug to the cells without inducing an enhancement of the efficacy of the drug.     

Reprogrammable Phononic Metasurfaces

Phononic metamaterials rely on the presence of resonances in a structured medium to control the propagation of elastic waves. Their response depends on the geometry of their fundamental building blocks. A major challenge in metamaterials design is the realization of basic building blocks that can be tuned dynamically. Here, a metamaterial plate is realized that can be dynamically tuned by harnessing geometric and magnetic nonlinearities in the individual unit cells. The proposed tuning mechanism allows a stiffness variability of the individual unit cells and can control the amplitude of transmitted excitation through the plate over three orders of magnitude. The concepts can be extended to metamaterials at different scales, and they can be applied in a broad range of engineering applications, from seismic shielding at low frequency to ultrasonic cloaking at higher frequency ranges.     

Highly Sensitive,Anisotropic, and Reversible Stress/Strain‐Sensors from Mechanochromic Nanofiber Composites

Mechanochromic polymeric systems are intensively investigated for real‐time stress detection applications. However, an effective stress‐sensing material must respond to low deformation with a detectable color change that should be quickly reversible upon force unloading. In this work, mechanochromic nanofibers made by electrospinning are used to produce mechanochromic nanofiber/poly(dimethylsiloxane) (PDMS) composites with isotropic and anisoptropic response. Due to chain alignment of spiropyran copolymer chains within the nanofibers, only very small strains are required to yield a mechanochromic response. Composites with aligned and isotropic nanofibers show anisotropic and isotropic mechanochromic behavior, respectively. Due to the special substitution pattern of spiropyran in the copolymer, the mechanochromic response of these nanofiber/PDMS composites shows fast reversibility upon force unloading. The outstanding benefit of using highly sensitive mechanochromic nanofibers as filler in composite materials allows the detection of directional stress and strain, and it is a step forward in the development of smart, mechanically responsive materials.     

Multicomponent crystals of gliclazide and tromethamine: preparation,physico-chemical,and pharmaceutical characterization*

Objective: To improve the pharmaceutical behavior of the oral antidiabetic agent gliclazide through the synthesis of multicomponent crystals with tromethamine.

Methods: Multicomponent crystals were prepared by solvent evaporation method, kneading, and combining mechanical and thermal activation. DSC, FT-IR spectroscopy, X-ray diffraction, SEM-EDS, and SSNMR were used to investigate their formation. Measurements of solubility and dissolution rate were carried out for the pharmaceutical characterization.

Results: The formation of multicomponent crystals of gliclazide and tromethamine was confirmed by all the techniques. In particular, FT-IR and NMR measurements revealed that the interaction between drug and coformer leads to significant changes of the hydrogen bond scheme, and that almost all the functional groups of the two molecules are involved. The dissolution profile of the new phase is significantly better than that of both pure gliclazide and of the reference commercial product Diabrezide^®.

Conclusions: The new system shows an improved pharmaceutical behavior and could be formulated in a dosage form to obtain a rapid and complete release of the drug available for absorption.     

Mild Innate Immune Activation Overrides Efficient Nanoparticle-Mediated RNA Delivery

Clinical mRNA delivery remains challenging, in large part because how physiology alters delivery in vivo remains underexplored. For example, mRNA delivered by lipid nanoparticles (LNPs) is being considered to treat inflammation, but whether inflammation itself changes delivery remains understudied. Relationships between immunity, endocytosis, and mRNA translation lead to hypothesize that toll-like receptor 4 (TLR4) activation reduced LNP-mediated mRNA delivery. Therefore, LNP uptake, endosomal escape, and mRNA translation with and without TLR4 activation are quantified. In vivo DNA barcoding is used to discover a novel LNP that delivers mRNA to Kupffer cells at clinical doses; unlike most LNPs, this LNP does not preferentially target hepatocytes. TLR4 activation blocks mRNA translation in all tested cell types, without reducing LNP uptake; inhibiting TLR4 or its downstream effector protein kinase R improved delivery. The discrepant effects of TLR4 on i) LNP uptake and ii) translation suggests TLR4 activation can “override” LNP targeting, even after mRNA is delivered into target cells. Given near-future clinical trials using mRNA to modulate inflammation, this highlights the need to understand inflammatory signaling in on- and off-target cells. More generally, this suggests an LNP which delivers mRNA to one inflammatory disease may not deliver mRNA to another.     

pp'DDE contamination of the blood and diet in central European populations

In this study, the actual risk of DDT pollution to two European human populations was assessed by analysing DDT residues in the diet, which is the main route of pollution for man, and in the blood and placenta, which are components affecting organs and new generations, respectively. The Gdańsk region was selected as representative of areas subjected to a recent DDT ban in Europe, while a rural area in Western Germany was considered representative of European regions where DDT use and production ceased many years ago. The results of three food series of food sampling carried out with market basket methods during 2003 showed that pp'DDE, which is by far the main constituent of DDT residues, was present in foods of animal origin and in cereals at rather high concentrations in both countries, and that a risk for human health cannot be excluded. The total daily intake was higher in Poland than in Germany, and agrees with the finding that body tissues, on the average, are more polluted in donors from Poland than those from Germany.     

Nanoelectrospray ion mobility spectrometry online with inductively coupled plasma-mass spectrometry for sizing large proteins, DNA, and nanoparticles

Recently it has been demonstrated that nanoelectrospray (nES) in conjunction with macro-ion mobility spectrometry (macroIMS) and condensed particle detection can be used to size various types of nanoparticles, including large biomolecules (proteins, DNA, etc.), having electrophoretic mobility diameters ranging from 3 nm to well over 100 nm. The technique is extremely sensitive; however, it lacks specificity as a result of the detector used. To explore the possibility to overcome this limitation, we demonstrate the direct coupling of the nES-macroIMS system to an inductively coupled plasma mass spectrometer (ICPMS). Technical challenges involving the coupling of the air-based nES-macroIMS with the argon-based ICPMS are addressed and overcome. The resulting novel hyphenated technique is used to determine the elemental composition of nanoparticles resulting from the electrospraying of solutions containing inorganic salts and acids (CsI and dimethylarsinic acid). Even though the sensitivity of the used ICPMS does not allow for the simultaneous sizing of proteins and the determination of their metal, metalloid, or halogen content, we have shown that it is feasible to detect and accurately size proteins at femtomole levels by adding CsI to their solutions and detecting the resulting Cs adducts. This is also possible with DNA molecules. A linear relationship between protein amount and ICPMS response for (133)Cs(+) is observed, thus hinting at the possibility of further developing the technique for quantitative analysis of large biomolecules.     

Biocompatible glass–ceramic materials for bone substitution

A new bioactive glass composition (CEL2) in the SiO₂–P₂O₅–CaO–MgO–K₂O–Na₂O system was tailored to control pH variations due to ion leaching phenomena when the glass is in contact with physiological fluids. CEL2 was prepared by a traditional melting-quenching process obtaining slices that were heat-treated to obtain a glass-ceramic material (CEL2GC) that was characterized thorough SEM analysis. Pre-treatment of CEL2GC with SBF was found to enhance its biocompatibility, as assessed by in vitro tests. CEL2 powder was then used to synthesize macroporous glass–ceramic scaffolds. To this end, CEL2 powders were mixed with polyethylene particles within the 300–600 μm size-range and then pressed to obtain crack-free compacted powders (green). This was heat-treated to remove the organic phase and to sinter the inorganic phase, leaving a porous structure. The biomaterial thus obtained was characterized by X-ray diffraction, SEM equipped with EDS, density measurement, image analysis, mechanical testing and in vitro evaluation, and found to be a glass–ceramic macroporous scaffold with uniformly distributed and highly interconnected porosity. The extent and size-range of the porosity can be tailored by varying the amount and size of the polyethylene particles.