-
BioRxiv : the Preprint Server For... Jun 2024About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor...
About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)--poly(propylene sulfide) (PEG--PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.
PubMed: 38948803
DOI: 10.1101/2024.06.11.598439 -
Micromachines Jun 2024This study developed a novel dielectric wetting microfluidic operation platform combining parallel-plate and coplanar-plate regions with a curved surface structure as...
This study developed a novel dielectric wetting microfluidic operation platform combining parallel-plate and coplanar-plate regions with a curved surface structure as the connection structure. With the new electrowetting on dielectric (EWOD) platform, "droplet pull-out" has been successfully achieved and viewed as an essential new operation for microfluidics with the dielectric wetting technique. The EWOD system is divided into a PDMS substrate top plate and an indium tin oxide (ITO) glass substrate as a bottom layer on this chip. In the parallel-plate region, the droplets can be generated and transported through the square parallel electrodes; in the single-plate area, the droplets can be pulled out from the parallel structure, transported and mixed through the common grounded coplanar electrodes. In dielectric wetting performance testing, coplanar electrodes can apply a maximum driving force of 31.22 µN to DI water and 13.38 µN to propylene carbonate (PC). This driving force is sufficient to detach the sample from the top cover and pull the sub-droplet from the parallel plate structure for DI water, PC and polyethylene glycol diacrylate (PEGDA) buffer. The novel EWOD system also possesses the advantage of precise volume control for liquid samples; the volume error of the generated droplet can be controlled within 0.1% to 2%.
PubMed: 38930767
DOI: 10.3390/mi15060797 -
Materials (Basel, Switzerland) Jun 2024Studying multiple properties of a material concurrently is essential for obtaining a comprehensive understanding of its behavior and performance. However, this approach...
Studying multiple properties of a material concurrently is essential for obtaining a comprehensive understanding of its behavior and performance. However, this approach presents certain challenges. For instance, simultaneous examination of various properties often necessitates extensive experimental resources, thereby increasing the overall cost and time required for research. Furthermore, the pursuit of desirable properties for one application may conflict with those needed for another, leading to trade-off scenarios. In this study, we focused on investigating adhesive joint strength and elastic modulus, both crucial properties directly impacting adhesive behavior. To determine elastic modulus, we employed a non-destructive indentation method for converting hardness measurements. Additionally, we introduced a specimen apparatus preparation method to ensure the fabrication of smooth surfaces and homogeneous polymeric specimens, free from voids and bubbles. Our experiments utilized a commercially available bisphenol A-based epoxy resin in combination with a Poly(propylene glycol) curing agent. We generated an initial dataset comprising experimental results from 32 conditions, which served as input for training a machine learning model. Subsequently, we used this model to predict outcomes for a total of 256 conditions. To address the high deviation in prediction results, we implemented active learning approaches, achieving a 50% reduction in deviation while maintaining model accuracy. Through our analysis, we observed a trade-off boundary (Pareto frontier line) between adhesive joint strength and elastic modulus. Leveraging Bayesian optimization, we successfully identified experimental conditions that surpassed this boundary, yielding an adhesive joint strength of 25.2 MPa and an elastic modulus of 182.5 MPa.
PubMed: 38930235
DOI: 10.3390/ma17122866 -
Dental Materials : Official Publication... Jun 2024The permeability of triamcinolone acetonide (TA), from bilayer mucoadhesive buccal films, through a biomimetic membrane, Permeapad™, was investigated employing Franz...
OBJECTIVES
The permeability of triamcinolone acetonide (TA), from bilayer mucoadhesive buccal films, through a biomimetic membrane, Permeapad™, was investigated employing Franz diffusion cell. The delivery systems composition and ethyl cellulose (EC) backing layer, on drug permeability, were assessed.
METHODS
Three TA-loaded films were tested; hydroxypropyl methylcellulose (HPMC K4M; bilayer [F1] and monolayer), HPMC K4M/Polyvinylpyrrolidone (PVP): 90/10 [F2], and HPMC K15M film [F3]. All films contained propylene glycol (PG-plasticiser). TA solution alone was used as a control. TA permeability via a Permeapad™ barrier, simulating buccal mucosa, was assessed over 8 h using a Franz diffusion cell. TA permeated into the receptor compartment, released in the donor compartment, and located on/within the Permeapad™ barrier were analysed using UV-spectrophotometer.
RESULTS
45.7 % drug retention within the Permeapad™ barrier was delivered from F1 (highest). F1, F2, and F3 significantly improved the TA's permeability through Permeapad™, compared to TA solution alone (e.g., 8.5 % TA-solution, 21.5 %-F1), attributed to the synergy effect of HPMC and propylene glycol acting as penetration enhancers. F1 displayed a significant increase in drug permeability (receptor compartment; 21.5 %) compared to F3 (17.0 %). PVP significantly enhanced drug permeability (27.5 %). Impermeable EC backing layer controlled unidirectional drug release and reduced drug loss into the donor compartment (e.g., ∼28 % for monolayer film to ∼10 % for bilayer film, F1).
SIGNIFICANCE
The mucoadhesive films demonstrated improved TA permeability via Permeapad™. The findings suggest that these bilayer mucoadhesive films, particularly F1, hold promise for the effective topical treatment of oral mucosa disorders, such as recurrent aphthous stomatitis and oral lichen planus.
PubMed: 38902145
DOI: 10.1016/j.dental.2024.06.016 -
Materials (Basel, Switzerland) Jun 2024The application of polyesters as food contact materials is an alternative to epoxy resin coatings, which can be a source of endocrine migrants. By using high-pressure...
The application of polyesters as food contact materials is an alternative to epoxy resin coatings, which can be a source of endocrine migrants. By using high-pressure liquid chromatography/electrospray ionization-mass spectrometry (HPLC/ESI-MS) with cone voltage-induced fragmentation in-source, a number of polyester-derived migrants were detected in the extracts of inner coatings of metallic cans. The polyester-derived migrants were detected in each inner coating of fish product-containing cans (5/5) and in one inner coating of meat product-containing can (1/5). They were not detected in the inner coatings of vegetable/fruit product-containing cans (10 samples). The respective detected parent and product ions enabled differentiation between cyclic and linear compounds, as well as unambiguous identification of diol and diacid units. Most of the detected compounds, cyclic and linear, were composed of neopentyl glycol as diol and two diacid comonomers, namely isophthalic acid and hexahydrophthalic acid. The other detected oligoesters were composed of neopentyl glycol or propylene glycol and adipic acid/isophthalic acid as comonomers. The compounds containing propylene glycol as diol were found to be exclusively linear cooligoesters. On the basis of abundances of [M+Na] ions, the relative contents of cyclic and linear oligoesters were evaluated.
PubMed: 38894033
DOI: 10.3390/ma17112771 -
Scientific Reports Jun 2024Propolis extracts have been used in traditional medicines since ages due to its advantageous complex chemical composition. However, the antibacterial and antifungal...
Propolis extracts have been used in traditional medicines since ages due to its advantageous complex chemical composition. However, the antibacterial and antifungal activity of poplar propolis extracts prepared in Natural Deep Eutectic Solvent (NADES) are seldom studied. This study investigates suitable alternate for ethanol as a solvent for extraction for Polish poplar propolis. It also attempts to identify suitable extraction condition for the efficient transfer of compounds from propolis to the solvents. The extraction efficiency of NADES extracts was assessed in terms of total phenolic content, antioxidant activity and antimicrobial activity. The chemical composition of the extracts was analysed using UHPLC-DAD-QqTOF-MS. Four extracts, prepared in Propylene Glycol, Choline Chloride:Propylene Glycol (1:3), Choline Chloride:Propylene Glycol (1:4) and Choline Chloride:Glycerol (1:2), demonstrated activity and properties similar to ethanolic extract and extraction at 50 °C was found the most suitable for propolis. HPLC analysis confirmed that the chemical cocktail extracted by these solvents from propolis were identical with minor variations in their concentration as compared to its ethanolic extract. Thus, extracts of propolis at 50 °C in Propylene Glycol, Choline Chloride:Propylene Glycol (1:3) and Choline Chloride:Propylene Glycol (1:4) can be alternates for ethanolic extracts.
Topics: Propolis; Antifungal Agents; Anti-Bacterial Agents; Microbial Sensitivity Tests; Chromatography, High Pressure Liquid; Plant Extracts; Antioxidants; Propylene Glycol; Solvents; Choline; Deep Eutectic Solvents; Phenols
PubMed: 38871855
DOI: 10.1038/s41598-024-64111-7 -
Langmuir : the ACS Journal of Surfaces... Jun 2024Flow-assisted alignment of anisotropic nanoparticles is a promising route for the bottom-up assembly of advanced materials with tunable properties. While aligning...
Flow-assisted alignment of anisotropic nanoparticles is a promising route for the bottom-up assembly of advanced materials with tunable properties. While aligning processes could be optimized by controlling factors such as solvent viscosity, flow deformation, and the structure of the particles themselves, it is necessary to understand the relationship between these factors and their effect on the final orientation. In this study, we investigated the flow of surface-charged cellulose nanocrystals (CNCs) with the shape of a rigid rod dispersed in water and propylene glycol (PG) in an isotropic tactoid state. scanning small-angle X-ray scattering (SAXS) and rheo-optical flow-stop experiments were used to quantify the dynamics, orientation, and structure of the assigned system at the nanometer scale. The effects of both shear and extensional flow fields were revealed in a single experiment by using a flow-focusing channel geometry, which was used as a model flow for nanomaterial assembly. Due to the higher solvent viscosity, CNCs in PG showed much slower Brownian dynamics than CNCs in water and thus could be aligned at lower deformation rates. Moreover, CNCs in PG also formed a characteristic tactoid structure but with less ordering than CNCs in water owing to weaker electrostatic interactions. The results indicate that CNCs in water stay assembled in the mesoscale structure at moderate deformation rates but are broken up at higher flow rates, enhancing rotary diffusion and leading to lower overall alignment. Albeit being a study of cellulose nanoparticles, the fundamental interplay between imposed flow fields, Brownian motion, and electrostatic interactions likely apply to many other anisotropic colloidal systems.
PubMed: 38859701
DOI: 10.1021/acs.langmuir.4c01846 -
Biomedical Optics Express May 2024Transdermal drug delivery patches are a good alternative to hypodermic drug injection. The drug delivery efficiency depends strongly on the hydration of the skin under...
Transdermal drug delivery patches are a good alternative to hypodermic drug injection. The drug delivery efficiency depends strongly on the hydration of the skin under treatment, and therefore, it is essential to study the effects on the skin induced by the application of these medical-grade patches. Terahertz (THz) spectroscopy shows great promise for non-invasive skin evaluation due to its high sensitivity to subtle changes in water content, low power and non-ionizing properties. In this work, we study the effects of transdermal drug delivery patches (three fully occlusive and three partially occlusive) applied on the upper arms of ten volunteers for a maximum period of 28 h. Three different levels of propylene glycol (0 %, 3 % and 6 %) are added to the patches as excipient. By performing multilayer analysis, we successfully retrieve the water content of the stratum corneum (SC) which is the outermost layer of skin, as well as its thickness at different times before and after applying the patches. This study demonstrates the potential of using THz sensing for non invasive skin monitoring and has wide applications for skin evaluation as well as the development of skin products.
PubMed: 38855675
DOI: 10.1364/BOE.513557 -
Scientific Reports Jun 2024The use of deicers in urban areas, on runways and aircrafts has raised concerns about their environmental impact. Understanding the ice-melting mechanism is crucial for...
The use of deicers in urban areas, on runways and aircrafts has raised concerns about their environmental impact. Understanding the ice-melting mechanism is crucial for developing environmentally friendly deicers, yet it remains challenging. This study employs machine learning to investigate the ice penetration capacity (IPC) of 21 salts and 16 organic solvents as deicers. Relationships between their IPC and various physical properties were analysed using extreme gradient boosting (XGBoost) and Shapley additive explanation (SHAP). Three key ice-melting mechanisms were identified: (1) freezing-point depression, (2) interactions between deicers and HO molecules and (3) infiltration of ions into ice crystals. SHAP analysis revealed different ice-melting factors and mechanisms for salts and organic solvents, suggesting a potential advantage in combining the two. A mixture of propylene glycol (PG) and sodium formate demonstrated superior environmental impact and IPC. The PG and sodium formate mixture exhibited higher IPC when compared to six commercially available deicers, offering promise for sustainable deicing applications. This study provides valuable insights into the ice-melting process and proposes an effective, environmentally friendly deicer that combines the strengths of organic solvents and salts, paving the way for more sustainable practices in deicing.
PubMed: 38849379
DOI: 10.1038/s41598-024-62942-y -
EMBO Molecular Medicine Jun 2024
PubMed: 38844556
DOI: 10.1038/s44321-024-00078-2