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Tunneling nanotubes (TNTs) are thin, dynamic, long membrane protrusions that allow intercellular exchanges of signaling clues, molecules and organelles. The presence of TNTs and their involvement as drug delivery channels have been observed in several types of cancer, including glioblastoma. Recently, increased attention has been directed toward nanoparticles (NPs) that can be transported in TNTs. However, few data are available on the role of physical parameters of nanoparticles, such as size, shape, charge and flexibility, in determining their transfer efficiency between cells by TNTs. Here, we focused our attention on NP shape, manufacturing spherical, discoidal and deformable negatively charged lipid-based NPs with sizes <120 nm and similar stiffness. The TNT-mediated transfer of NPs was investigated in 2D and 3D culture models of human glioblastoma cells. The permeability and biocompatibility of the blood–brain barrier (BBB) were also assessed. Results showed that discoidal NPs displayed the highest TNT-mediated transfer efficiency between cancer cells, with a maximum velocity of 69 nm s−1, and a higher endothelial permeability (1.29 × 10−5 cm min−1) across the BBB in an in vitro model. This depends on the NP shape because discoidal NPs have a larger surface area exposed to the flow along the TNT channel. Overall, the results suggest that the shape of NPs is the game-changer for more efficient TNT-mediated transfer between cancer cells, thus introducing a sustainable solution to improve the diffusion rate at which the NPs spread in the tumour microenvironment, opening the possibility of ameliorating drug distribution to difficult-to-reach cancer cell populations.
Skin equivalents (SE) that recapitulate biological and mechanical characteristics of the native tissue are promising platforms for assessing cosmetics and studying fundamental biological processes. Methods to achieve SEs with well-organized structure, and ideal biological and mechanical properties are limited. Here, the combination of melt electrowritten PCL scaffolds and cell-laden Matrigel to fabricate SE is described. The PCL scaffold provides ideal structural and mechanical properties, preventing deformation of the model. The model consists of a top layer for seeding keratinocytes to mimic the epidermis, and a bottom layer of Matrigel-based dermal compartment with fibroblasts. The compressive modulus and the biological properties after 3-day coculture indicate a close resemblance with the native skin. Using the SE, a testing system to study the damage caused by UVA irradiation and evaluate antioxidant efficacy is established. The effectiveness of Tea polyphenols (TPs) and L-ascorbic acid (Laa) is compared based on free radical generation. TPs are demonstrated to be more effective in downregulating free radical generation. Further, T1 relaxometry is used to detect the generation of free radicals at a single-cell level, which allows tracking of the same cell before and after UVA treatment.
The laser welding of Cu–Al alloys for battery applications in the automotive industry presents significant challenges due to the high reflectivity of copper. Inadequate bonding and low mechanical strength may occur when the laser radiation is directed toward the copper side in an overlap configuration welding. To tackle these challenges, a laser surface treatment technique is implemented to enhance the absorption characteristics and overcome the reflective nature of the copper material. However, elevating the surface roughness and heat-energy input over threshold values leads to heightened temperature and extreme weld. This phenomenon escalates the formation of detrimental intermetallic compounds (IMC), creating defects like cracks and porosity. Metallurgical analysis, which is time-consuming and expensive, is usually used in studies to detect these phases and defects. However, to comprehensively evaluate the weld quality and discern the impact of surface structure, adopting a more innovative approach that replaces conventional cross-sectional metallography is essential. This article proposes a model based on the image feature extraction of the welds to study the effect of the laser-based structure and the other laser parameters. It can detect defects and identify the weld quality by weld classification. However, due to the complexity of the photo features, the system requires image processing and a convolutional neural network (CNN). Results show that the predictive model based on trained data can detect different weld categories and recognize unstable welds. The project aims to use a monitoring model to guarantee optimized and high-quality weld series production. To achieve this, a deeper study of the parameters and the microstructure of the weld is utilized, and the CNN model analyzes the features of 1310 pieces of weld photos with different weld parameters.
Uric acid detection by hydrogen peroxide independent biosensors: Novel insights and applications
(2024)
Uric acid (UA) is one of the most electroactive low molecular weight compounds that can be electrochemically oxidized on the surfaces of numerous noble and non-noble electrocatalysts under applied polarization. Consequently, enzymatic determination of UA in model and real samples is complicated by possible interference between electrochemical and biochemical routes. Herein, a novel strategy for amperometric enzymatic hydrogen peroxide independent UA sensing at low concentrations (e.g., below 50 µM) is proposed. The UA-sensitive strategy relies on the use of screen printed electrodes modified by an electrodeposited hybrid functional sensing film comprising a non-noble electrocatalyst, a bioorganic layer containing enzyme uricase (UOx), and data acquisition enabling the biochemical transformation of UA to be distinguished from the electrochemical oxidation route. Performed selectivity test utilizing adenine, xanthine, urea, ascorbic acid, ethanol and glycerol did not reveal interferences during detection of UA. This proposed approach was tested for UA detection in model and fermentation samples. The quantitative results obtained in fermentation samples were validated through optical oxygen mini sensor studies and fluorescence-based bioassays.
The dragonfish is a voracious predator of the deep sea with an arsenal of tools to hunt prey and remain concealed. In contrast to its dark pigmented skin, the dragonfish is equipped with transparent teeth. Here, we establish the structure, composition, and mechanical properties of the transparent teeth for the first time. We find the enamel-like layer to consist of nanocrystalline hydroxyapatite domains (∼20 nm grain size) embedded in an amorphous matrix, whereas in the dentin layer the nanocrystalline hydroxyapatite coats nanoscale collagen fibrils forming nanorods. This nanoscale structure is responsible for the much-reduced Rayleigh light scattering, which is further ensured by the sufficiently thin walls. Here, we suggest that the nanostructured design of the transparent dragonfish teeth enables predatory success as it makes its wide-open mouth armed with saber-like teeth effectively disappear, showing no contrast to the surrounding blackness of the fish nor the background darkness of the deep sea.
Nanostructured lipid carrier formulation for delivering poorly water-soluble ITF3756 HDAC inhibitor
(2024)
Histone deacetylases (HDACs) are enzymes that play crucial roles in cellular processes by hydrolyzing acetyl-L-lysine side chains in core histones, thereby regulating gene expression and maintaining homeostasis. Histone deacetylase inhibitors (HDACi) have emerged as promising agents, particularly in cancer treatment, due to their ability to induce cytotoxic and pro-apoptotic effects. Selective HDAC6 inhibitors, such as ITF3756, have shown low off-target toxicity and promising pharmacological activities, but their poor water solubility limits their application in nanoparticulate drug delivery systems. Here, we optimized a nanostructured lipid carrier (NLC) formulation for delivering ITF3756 using the design of experiments (DOE) and response surface methodology (RSM). An interaction between the factor surfactant and formulation volume was observed, thus demonstrating that the surfactant concentration impacts the NLC size. It can be speculated that the higher the amount of the drug in the formulation, the lower the polydispersion index (PDI), thus resulting in more stable nanostructures. The optimized ITF3756-NLC demonstrated a size of 51.1 ± 0.3 nm, 8.85 ± 4.71 mV charge, and high entrapment efficiency (EE%), maintaining stability for 60 days. Moreover, ITF3756-NLC enhanced α-tubulin acetylation in melanoma, lung, and brain cancer cell lines, indicating retained or improved bioactivity. The ITF3756-NLC formulation offers a viable approach for enhancing the bioavailability and therapeutic efficacy of HDAC6 inhibitors, demonstrating potential for clinical applications in cancer immunotherapy.
Pseudomonas aeruginosa (PA) is a major healthcare concern due to its tolerance to antibiotics when enclosed in biofilms. Tobramycin (Tob), an effective cationic aminoglycoside antibiotic against planktonic PA, loses potency within PA biofilms due to hindered diffusion caused by interactions with anionic biofilm components. Loading Tob into nano-carriers can enhance its biofilm efficacy by shielding its charge. Polyion complex vesicles (PIC-somes) are promising nano-carriers for charged drugs, allowing higher drug loadings than liposomes and polymersomes. In this study, a new class of nano-sized PIC-somes, formed by Tob-diblock copolymer complexation is presented. This approach replaces conventional linear PEG with brush-like poly[ethylene glycol (methyl ether methacrylate)] (PEGMA) in the shell-forming block, distinguishing it from past methods. Tob paired with a block copolymer containing hydrophilic PEGMA induces micelle formation (PIC-micelles), while incorporating hydrophobic pyridyldisulfide ethyl methacrylate (PDSMA) monomer into PEGMA chains reduces shell hydrophilicity, leads to the formation of vesicles (PIC-somes). PDSMA unit incorporation enables unprecedented dynamic disulfide bond-based shell cross-linking, significantly enhancing stability under saline conditions. Neither PIC-somes nor PIC-micelles show any relevant cytotoxicity on A549, Calu-3, and dTHP-1 cells. Tob's antimicrobial efficacy against planktonic PA remains unaffected after encapsulation into PIC-somes and PIC-micelles, but its potency within PA biofilms significantly increases.
Nominal CaAl2Pt2 and Ca2Al3Pt – two new Intermetallic Compounds in the Ternary System Ca−Al−Pt
(2024)
Single crystals of CaAl2Pt2, Ca2Al3Pt and Ca2AlPt2 were initially observed in an attempt to synthesize Ca3Al4Pt4. Their structures were determined using single-crystal X-ray diffraction experiments. While nominal CaAl2Pt2 (CaBe2Ge2 type, P4/nmm, a=426.79(2), c=988.79(6) pm, wR2=0.0679, 246 F2 values and 18 variables) and Ca2Al3Pt (Mg2Cu3Si type, P63/mmc, a=561.46(5), c=876.94(8) pm, wR2=0.0664, 214 F2 values and 13 variables) exhibit Al/Pt mixing, for Ca2AlPt2 (Ca2Ir2Si type, C2/c, a=981.03(2) b=573.74(1), c=772.95(2) pm, β=101.862(1)° wR2=0.0307, 2246 F2 values and 25 variables) no mixing was observed. Subsequently, the nominal compositions were targeted with synthetic attempts from the elements using arc-melting and annealing techniques. For CaAl2Pt2 and Ca2Al3Pt always multi-phase mixtures were observed while Ca2AlPt2 could be obtained as almost X-ray pure material. Quantum-chemical calculations were used to investigate the charge transfer in these compounds rendering them polar intermetallics with a designated [AlxPty]δ− polyanion and Caδ+ cations in the cavities of the polyanions.
Cobaltocenium-containing polymers, an emerging class of materials, have historically been challenging to prepare due to their chemical robustness. In this work, we introduce a novel and highly efficient method for their preparation based on methacrylate-containing block copolymers (BCPs), allowing segment-selective introduction of functional moieties. The catalyst-free and quantitative hydroamination reaction we introduce has proven successful for the post-modification of amine-containing polymers with cobaltocenium. To demonstrate the versatility of this method, we successfully synthesized a series of BCPs consisting of polystyrene and a 5 to 20 wt% poly(tert-butyl aminoethyl methacrylate) (PtBAEMA) segment by living anionic polymerization. The selective functionalization with ethynyl-cobaltocenium hexafluorophosphate results in adjustable 5 to 40 wt% cobaltocenium units in the polymer as part of the PtBAEMA block segment. The success was monitored by IR spectroscopy, and the quantitative incorporation of the cobaltocenium moiety was verified by 1H NMR, UV-Vis spectroscopy, and TGA. DSC proved the block-selective cobaltocenium introduction by an additional glass transition temperature at 154 °C, and the strong microphase separation character of the amphiphilic BCPs leads to lamellar structures in the bulk state, as proven by TEM investigations. Finally, the water contact angle on polymer films is compared, showing polarity inversion and tunability upon conversion of hydrophilic amine to hydrophobic cobaltocenium hexafluorophosphate moieties. This successful synthesis and characterization of cobaltocenium-containing BCPs not only paves the way for a new class of metallopolymers but also offers functionalization possibilities for a variety of other responsive moieties, providing access to functional BCPs.
The expansion of T cells ex vivo is crucial for effective immunotherapy but currently limited by a lack of expansion approaches that closely mimic in vivo T cell activation. Taking inspiration from bottom-up synthetic biology, a new synthetic cell technology is introduced based on dispersed liquid-liquid phase-separated droplet-supported lipid bilayers (dsLBs) with tunable biochemical and biophysical characteristics, as artificial antigen presenting cells (aAPCs) for ex vivo T cell expansion. These findings obtained with the dsLB technology reveal three key insights: first, introducing laterally mobile stimulatory ligands on soft aAPCs promotes expansion of IL-4/IL-10 secreting regulatory CD8+ T cells, with a PD-1 negative phenotype, less prone to immune suppression. Second, it is demonstrated that lateral ligand mobility can mask differential T cell activation observed on substrates of varying stiffness. Third, dsLBs are applied to reveal a mechanosensitive component in bispecific Her2/CD3 T cell engager-mediated T cell activation. Based on these three insights, lateral ligand mobility, alongside receptor- and mechanosignaling, is proposed to be considered as a third crucial dimension for the design of ex vivo T cell expansion technologies.