Transdermal Delivery of Cytochrome C—A 12.4kDa Protein—Across Intact Skin by Constant-Current Iontophoresis

Purpose: To demonstrate the transdermal iontophoretic delivery of a small (12.4kDa) protein across intact skin. Materials and Methods: The iontophoretic transport of Cytochrome c (Cyt c) across porcine ear skin in vitro was investigated and quantified by HPLC. The effect of protein concentration (0.35 and 0.7mM), current density (0.15, 0.3 or 0.5mA.cm−2 applied for 8h) and competing ions was evaluated. Co-iontophoresis of acetaminophen was employed to quantify the respective contributions of electromigration (EM) and electroosmosis (EO). Results: The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for ∼90% of delivery; correlation between EM flux and electrophoretic mobility was consistent with earlier results using small molecules. Modest EO inhibition was observed at 0.5mA.cm−2. Cumulative permeation at 0.3 and 0.5mA.cm−2 was significantly greater than that at 0.15mA.cm−2; fluxes using 0.35 and 0.7mM Cyt c in the absence of competing ions (J tot  = 182.8 ± 56.8 and 265.2 ± 149.1μg.cm−2.h−1, respectively) were statistically equivalent. Formulation in PBS (pH8.2) confirmed the impact of competing charge carriers; inclusion of ∼170mM Na+ resulted in a 3.9-fold decrease in total flux. Conclusions: Significant amounts (∼0.9mg.cm−2 over 8h) of Cyt c were delivered non-invasively across intact skin by transdermal electrotranspor

Polymer-lipid nanoparticles for systemic delivery of mRNA to the lungs

Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β‐amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer–lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer–lipid nanoparticles

Editorial to Special Issue “Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective”

Glioblastoma (GBM) remains the most common and aggressive malignant primary brain tumor [...

Editorial to Special Issue “Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective”

Glioblastoma (GBM) remains the most common and aggressive malignant primary brain tumor [...

Estudio del ITS nuclear en algunas especies del género Cantharellus de México

Las especies del gE?nero Cantharellus son de gran importancia econU?mica y ecolU?gica. Sin embargo, la variaciU?n morfolU?gica inter e intraespecI?fica de este gE?nero ha dificultado la ubicaciU?n taxonU?mica de algunas de sus especies, incluyendo la especie tipo. Por lo anterior, se llevU? a cabo un estudio taxonU?mico molecular. El ITS de 35 colectas y cinco Referencias cultivos puros de Cantharellus, provenientes del cen- tro, sur y norte de ME?xico, fue analizado mediante el uso de PCR (reacciU?n en cadena de la polimerasa) y RFLP (polimorfismo de la longitud de los fragmen- tos de restricciU?n). Las especies estudiadas fueron: C. cibarius, C. lateritius, C. minor, C. cinnabarinus, C. aff. amethysteus, Cantharellus spp. y Cr. cinereus (=C. cinereus). El RFLP no demostrU? suficiente reso- luciU?n para observar variaciU?n inter e intraespecI?fica, pero sI? demostrU? diferencias en cinco cultivos puros de Cantharellus

High-Speed Quenching of High Carbon Steel

Medium and high carbon steels are usually quenched in polymer and oil in order to avoid cracking and distortion; however, recent studies have proved that it is possible to minimize cracking using water as a coolant of these steels by promoting extremely high cooling rates. By great agitation and velocity of quenchant, the vapor blanket is reduced or prevented during water quench, allowing uniform hardening of the surface. In this study, the cooling severity of a spray quenching system and a high-speed quenching chamber are studied. Cylindrical samples of AISI 304 stainless steel (20 mm in diameter and 100 mm length) were employed to characterize the cooling severity. Thermal data was acquired through K-type thermocouples placed in the sample at three positions, 1 mm below surface, mid-radius and at center of the specimen, connected to a data acquisition system. High thermal gradients were observed in both systems, being the high-speed chamber the severest cooling. The maximum cooling rate obtained at the surface was 470 and 300°C/s for the high-speed chamber and the spray system, respectively. In addition, 5160 spring steel samples were quenched for short times in both systems; the cooling was interrupted to avoid through transformation and to produce a case-core type microstructure. Different cooling times were used for the interrupted quenching to modify the martensite case thickness. No cracks were observed. Thermal results and microstructures are discussed

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.This work was funded by grants from the Andalusian Regional Ministry of Health (PI 0272-2017 to V.C.-G), the Institute of Health Carlos III co-funded by Fondos FEDER (PI20/00341, CP19/00046 to V.C.-G; PI18/01590, CPII19/00023 to A.M.-M.), the Fundación Científica de la Aso ciación Española Contra el Cáncer (IDEAS20051CAPI to V.C.-G.), the crowdfunding platform PRE CIPITA of the Spanish Foundation for Science and Technology (2018-000237 to V.C.-G.), and the Asociación Pablo Ugarte (+ VIDA project to V.C.-G).Ye

Anti-Pathogenic Properties of the Combination of a T3SS Inhibitory Halogenated Pyrrolidone with C-30 Furanone

Antimicrobial resistance is one of the current public health challenges to be solved. The World Health Organization (WHO) has urgently called for the development of strategies to expand the increasingly limited antimicrobial arsenal. The development of anti-virulence therapies is a viable option to counteract bacterial infections with the possibility of reducing the generation of resistance. Here we report on the chemical structures of pyrrolidones DEXT 1–4 (previously identified as furan derivatives) and their anti-virulence activity on Pseudomonas aeruginosa strains. DEXT 1–4 were shown to inhibit biofilm formation, swarming motility, and secretion of ExoU and ExoT effector proteins. Also, the anti-pathogenic property of DEXT-3 alone or in combination with furanone C-30 (quorum sensing inhibitor) or MBX-1641 (type III secretion system inhibitor) was analyzed in a model of necrosis induced by P. aeruginosa PA14. All treatments reduced necrosis; however, only the combination of C-30 50 µM with DEXT-3 100 µM showed significant inhibition of bacterial growth in the inoculation area and systemic dispersion. In conclusion, pyrrolidones DEXT 1–4 are chemical structures capable of reducing the pathogenicity of P. aeruginosa and with the potential for the development of anti-virulence combination therapies