Rational Design and Development of Polymeric Nanogels as Protein Carriers.

Proteins have gained significant attention as potential therapeutic agents owing to their high specificity and reduced toxicity. Nevertheless, their clinical utility is hindered by inherent challenges associated with stability during storage and after in vivo administration. To overcome these limitations, polymeric nanogels (NGs) have emerged as promising carriers. These colloidal systems are capable of efficient encapsulation and stabilization of protein cargoes while improving their bioavailability and targeted delivery. The design of such delivery systems requires a comprehensive understanding of how the synthesis and formulation processes affect the final performance of the protein. This review highlights critical aspects involved in the development of NGs for protein delivery, with specific emphasis on loading strategies and evaluation techniques. For example, factors influencing loading efficiency and release kinetics are discussed, along with strategies to optimize protein encapsulation through protein-carrier interactions to achieve the desired therapeutic outcomes. The discussion is based on recent literature examples and aims to provide valuable insights for researchers working toward the advancement of protein-based therapeutics.

Preparation of Vancomycin-Loaded Aerogels Implementing Inkjet Printing and Superhydrophobic Surfaces.

Chronic wounds are physical traumas that significantly impair the quality of life of over 40 million patients worldwide. Aerogels are nanostructured dry porous materials that can act as carriers for the local delivery of bioactive compounds at the wound site. However, aerogels are usually obtained with low drug loading yields and poor particle size reproducibility and urges the implementation of novel and high-performance processing strategies. In this work, alginate aerogel particles loaded with vancomycin, an antibiotic used for the treatment of Staphylococcus aureus infections, were obtained through aerogel technology combined with gel inkjet printing and water-repellent surfaces. Alginate aerogel particles showed high porosity, large surface area, a well-defined spherical shape and a reproducible size (609 ± 37 µm). Aerogel formulation with vancomycin loadings of up to 33.01 ± 0.47 µg drug/mg of particle were obtained with sustained-release profiles from alginate aerogels for more than 7 days (PBS pH 7.4 medium). Overall, this novel green aerogel processing strategy allowed us to obtain nanostructured drug delivery systems with improved drug loading yields that can enhance the current antibacterial treatments for chronic wounds.

Supercritical CO2 sterilization: An effective treatment to reprocess FFP3 face masks and to reduce waste during COVID-19 pandemic.

The outbreak of COVID-19 pandemic unveiled an unprecedented scarcity of personal protective equipment (PPE) available in sanitary premises and for the population worldwide. This situation fostered the development of new strategies to reuse PPE that would ensure sterility and, simultaneously, preserve the filtering properties of the materials. In addition, the reuse of PPEs by reprocessing could reduce the environmental impact of the massive single-use and disposal of these materials. Conventional sterilization techniques such as steam or dry heat, ethylene oxide, and gamma irradiation may alter the functional properties of the PPEs and/or leave toxic residues. Supercritical CO2 (scCO2)-based sterilization is herein proposed as a safe, sustainable, and rapid sterilization method for contaminated face masks while preserving their performance. The functional (bacterial filtration efficiency, breathability, splash resistance, straps elasticity) properties of the processed FFP3 face masks were evaluated after 1 and 10 cycles of sterilization. Log-6 sterilization reduction levels were obtained for face masks contaminated with Bacillus pumilus endospores at mild operating conditions (CO2 at 39 °C and 100 bar for 30 min) and with low contents of H2O2 (150 ppm). Physicochemical properties of the FFP3 face masks remained unchanged after reprocessing and differences in efficacy were not observed neither in the filtration tests, following UNE-EN 14683, nor in the integrity of FFP3 filtration after the sterilization process. The herein presented method based on scCO2 technology is the first reported protocol achieving the reprocessing of FFP3 masks up to 10 cycles while preserving their functional properties.

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study.

BACKGROUND: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. PATIENTS AND METHODS: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. RESULTS: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data. CONCLUSIONS: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.

A Pathway From Porous Particle Technology Toward Tailoring Aerogels for Pulmonary Drug Administration.

Pulmonary drug delivery has recognized benefits for both local and systemic treatments. Dry powder inhalers (DPIs) are convenient, portable and environmentally friendly devices, becoming an optimal choice for patients. The tailoring of novel formulations for DPIs, namely in the form of porous particles, is stimulating in the pharmaceutical research area to improve delivery efficiency. Suitable powder technological approaches are being sought to design such formulations. Namely, aerogel powders are nanostructured porous particles with particularly attractive properties (large surface area, excellent aerodynamic properties and high fluid uptake capacity) for these purposes. In this review, the most recent development on powder technologies used for the processing of particulate porous carriers are described via updated examples and critically discussed. A special focus will be devoted to the most recent advances and uses of aerogel technology to obtain porous particles with advanced performance in pulmonary delivery.

Outcomes of systemic targeted therapy in recurrent renal cell carcinoma treated with adjuvant sunitinib.

OBJECTIVE: To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting. METHODS: In this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS). RESULTS: A total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2-20.4) months from diagnosis, and 7.5 months (1.0-8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78-18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4-41.8). CONCLUSIONS: Rechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib.

The AEROPILs Generation: Novel Poly(Ionic Liquid)-Based Aerogels for CO2 Capture.

CO2 levels in the atmosphere are increasing exponentially. The current climate change effects motivate an urgent need for new and sustainable materials to capture CO2. Porous materials are particularly interesting for processes that take place near atmospheric pressure. However, materials design should not only consider the morphology, but also the chemical identity of the CO2 sorbent to enhance the affinity towards CO2. Poly(ionic liquid)s (PILs) can enhance CO2 sorption capacity, but tailoring the porosity is still a challenge. Aerogel's properties grant production strategies that ensure a porosity control. In this work, we joined both worlds, PILs and aerogels, to produce a sustainable CO2 sorbent. PIL-chitosan aerogels (AEROPILs) in the form of beads were successfully obtained with high porosity (94.6-97.0%) and surface areas (270-744 m2/g). AEROPILs were applied for the first time as CO2 sorbents. The combination of PILs with chitosan aerogels generally increased the CO2 sorption capability of these materials, being the maximum CO2 capture capacity obtained (0.70 mmol g-1, at 25 °C and 1 bar) for the CHT:P[DADMA]Cl30%AEROPIL.

Modeling of the Production of Lipid Microparticles Using PGSS® Technique.

Solid lipid microparticles (SLMPs) are attractive carriers as delivery systems as they are stable, easy to manufacture and can provide controlled release of bioactive agents and increase their efficacy and/or safety. Particles from Gas-Saturated Solutions (PGSS®) technique is a solvent-free technology to produce SLMPs, which involves the use of supercritical CO2 (scCO2) at mild pressures and temperatures for the melting of lipids and atomization into particles. The determination of the key processing variables is crucial in PGSS® technique to obtain reliable and reproducible microparticles, therefore the modelling of SLMPs production process and variables control are of great interest to obtain quality therapeutic systems. In this work, the melting point depression of a commercial lipid (glyceryl monostearate, GMS) under compressed CO2 was studied using view cell experiments. Based on an unconstrained D-optimal design for three variables (nozzle diameter, temperature and pressure), SLMPs were produced using the PGSS® technique. The yield of production was registered and the particles characterized in terms of particle size distribution. Variable modeling was carried out using artificial neural networks and fuzzy logic integrated into neurofuzzy software. Modeling results highlight the main effect of temperature to tune the mean diameter SLMPs, whereas the pressure-nozzle diameter interaction is the main responsible in the SLMPs size distribution and in the PGSS® production yield.

Lidocaine-Loaded Solid Lipid Microparticles (SLMPs) Produced from Gas-Saturated Solutions for Wound Applications.

The delivery of bioactive agents using active wound dressings for the management of pain and infections offers improved performances in the treatment of wound complications. In this work, solid lipid microparticles (SLMPs) loaded with lidocaine hydrochloride (LID) were processed and the formulation was evaluated regarding its ability to deliver the drug at the wound site and through the skin barrier. The SLMPs of glyceryl monostearate (GMS) were prepared with different LID contents (0, 1, 2, 4, and 10 wt.%) using the solvent-free and one-step PGSS (Particles from Gas-Saturated Solutions) technique. PGSS exploits the use of supercritical CO2 (scCO2) as a plasticizer for lipids and as pressurizing agent for the atomization of particles. The SLMPs were characterized in terms of shape, size, and morphology (SEM), physicochemical properties (ATR-IR, XRD), and drug content and release behavior. An in vitro test for the evaluation of the influence of the wound environment on the LID release rate from SLMPs was studied using different bioengineered human skin substitutes obtained by 3D-bioprinting. Finally, the antimicrobial activity of the SLMPs was evaluated against three relevant bacteria in wound infections (Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa). SLMPs processed with 10 wt.% of LID showed a remarkable performance to provide effective doses for pain relief and preventive infection effects.

Jet Cutting Technique for the Production of Chitosan Aerogel Microparticles Loaded with Vancomycin.

Biopolymer-based aerogels can be obtained by supercritical drying of wet gels and endowed with outstanding properties for biomedical applications. Namely, polysaccharide-based aerogels in the form of microparticles are of special interest for wound treatment and can also be loaded with bioactive agents to improve the healing process. However, the production of the precursor gel may be limited by the viscosity of the polysaccharide initial solution. The jet cutting technique is regarded as a suitable processing technique to overcome this problem. In this work, the technological combination of jet cutting and supercritical drying of gels was assessed to produce chitosan aerogel microparticles loaded with vancomycin HCl (antimicrobial agent) for wound healing purposes. The resulting aerogel formulation was evaluated in terms of morphology, textural properties, drug loading, and release profile. Aerogels were also tested for wound application in terms of exudate sorption capacity, antimicrobial activity, hemocompatibility, and cytocompatibility. Overall, the microparticles had excellent textural properties, absorbed high amounts of exudate, and controlled the release of vancomycin HCl, providing sustained antimicrobial activity.

Design of Aerogels, Cryogels and Xerogels of Alginate: Effect of Molecular Weight, Gelation Conditions and Drying Method on Particles' Micromeritics.

Processing and shaping of dried gels are of interest in several fields like alginate aerogel beads used as highly porous and nanostructured particles in biomedical applications. The physicochemical properties of the alginate source, the solvent used in the gelation solution and the gel drying method are key parameters influencing the characteristics of the resulting dried gels. In this work, dried gel beads in the form of xerogels, cryogels or aerogels were prepared from alginates of different molecular weights (120 and 180 kDa) and concentrations (1.25, 1.50, 2.0 and 2.25% (w/v)) using different gelation conditions (aqueous and ethanolic CaCl2 solutions) and drying methods (supercritical drying, freeze-drying and oven drying) to obtain particles with a broad range of physicochemical and textural properties. The stability of physicochemical properties of alginate aerogels under storage conditions of 25 °C and 65% relative humidity (ICH-climatic zone II) during 1 and 3 months was studied. Results showed significant effects of the studied processing parameters on the resulting alginate dried gel properties. Stability studies showed small variations in aerogels weight and specific surface area after 3 months of storage, especially, in the case of aerogels produced with medium molecular weight alginate.

Vancomycin-loaded chitosan aerogel particles for chronic wound applications.

Chronic wounds are a prevailing cause of decreased quality of life, being microbial burden a factor hindering the normal wound healing process. Aerogels are nanostructured materials with large surface area (>250 m2/g) and high porosity (>96%). In this work, vancomycin-loaded chitosan aerogel beads were tested as a potential formulation to treat and prevent infections at the wound site. Processing of chitosan in the form of aerogels endowed this polysaccharide with enhanced water sorption capacity and air permeability. The morphological and textural properties of the particles were studied by image and N2 adsorption-desorption analysis and scanning electron microscopy. Vancomycin content and release profiles from aerogel carriers showed a fast drug release that permitted to efficiently achieve local therapeutic levels. Cell studies with fibroblasts and antimicrobial tests against S. aureus showed that the vancomycin-loaded aerogel particles were cytocompatible and effective in preventing high bacterial loads at the wound site.

Generation of highly enriched populations of optic vesicle-like retinal cells from human pluripotent stem cells.

The protocol outlined below is used to differentiate human pluripotent stem cells (hPSCs) into retinal cell types through a process that faithfully recapitulates the stepwise progression observed in vivo. From pluripotency, cells are differentiated to a primitive anterior neural fate, followed by progression into two distinct populations of retinal progenitors and forebrain progenitors, each of which can be manually separated and purified. The hPSC-derived retinal progenitors are found to self-organize into three-dimensional optic vesicle-like structures, with each aggregate possessing the ability to differentiate into all major retinal cell types. The ability to faithfully recapitulate the stepwise in vivo development in a three-dimensional cell culture system allows for the study of mechanisms underlying human retinogenesis. Furthermore, this methodology allows for the study of retinal dysfunction and disease modeling using patient-derived cells, as well as high-throughput pharmacological screening and eventually patient-specific therapies.

Pseudoporfiria en paciente dializada / Pseudoporphyria in a dialyzed patient

Se presenta el caso de una paciente de 34 años de edad con insuficiencia renal crónica de varios años de evolución. A los 6 meses de empezar el tratamiento con hemodiálisis presentó lesiones clínica e histológicamente características de pseudoporfiria. A su vez presentaba niveles normales de porfirinas en sangre. Se inició el tratamiento con N-acetilcisteína a razón de 600 mg dos veces al día (AU)

Nevo poroqueratósico de los ostios y ductos ecrinos / Porokeratotic eccrine ostial and dermal duct nevus

Se considera que el nevo poroqueratósico de los ostios y ductos ecrinos (NPODE) es un hamartoma del conducto sudoríparo. Presentamos el caso de una niña de un mes de edad que presentaba desde el nacimiento una erupción distribuida según las líneas de Blaschko en las extremidades y el tronco, con clara afectación palmoplantar. No se acompañaba de ningún otro defecto congénito y la paciente presentaba un desarrollo normal. La biopsia de una de las lesiones mostró los hallazgos típicos del nevo poroqueratósico de los ostios y ductos ecrinos. La anatomía patológica y las técnicas de inmunohistoquímica en este trastorno parecen revelar que la invaginación epidérmica en donde se halla la lámina paraqueratósica (similar a una lamela cornoide) es atravesada por un acrosiringio aparentemente normal. Dada la distribución de las lesiones y su aparición esporádica, el trastorno parece representar un mosaicismo genético (AU)

Pénfigo IgA / IgA pemphigus

El pénfigo IgA es una dermatosis ampollosa, caracterizada por la presencia de lesiones vesiculosas y pustulosas, junto con depósito de IgA en los espacios intercelulares de la epidermis superficial. Se distinguen dos tipos de pénfigo IgA: el tipo dermatosis pustulosa subcórnea y el tipo dermatosis IgA neutrofílica intraepidérmica. La dapsona es el tratamiento de elección en el pénfigo IgA, pero en ocasiones hay que añadir acitretín, colchicina, isotretinoína o corticoides sistémicos.Aportamos 2 casos de pénfigo IgA del tipo dermatosis pustulosa subcórnea (AU)

Sarcoidosis cicatrizal / Scar Sarcoidosis

La afectación cutánea en forma de sarcoidosis cicatrizal representa una de las formas más inusuales de la sarcoidosis cutánea. Se presenta el caso de una mujer de 56 años con cambios en antiguas cicatrices como forma de inicio de una sarcoidosis sistémica. La paciente presentaba infiltración violácea en algunas de sus antiguas cicatrices, previamente estables. Mediante estudio histopatológico se observaron granulomas de células epitelioides en dermis superficial y parte de dermis reticular. Las lesiones fueron progresando y afectaron también piel sana coincidiendo con el desarrollo de una uveítis anterior bilateral. El cuadro se controló con corticoides oftálmicos tópicos y cloroquina. La patogenia de sarcoidosis cicatrizal parece detenerse a una reacción de hipersensibilidad en la que el macrófago previamente estimulado por una sustancia inerte contaminante de la herida se reactiva por la sarcoidosis, infiltrando así dichas cicatrices antiguas (AU)

Ictiosis adquirida en paciente con neumotórax espontáneo / No disponible

No disponible

Dermatitis artefacta?

A 35-year-old man presented with a 2-month history of intensely pruritic excoriated and crusted linear lesions on the dorsa of the left hand and left forearm (Fig 1). The patient had worked in construction for 2 years, and his job consisted mainly in covering the facades of buildings with cement. The patient was right-handed and used a black rubber glove as a protective measure only on his left hand (Fig 2). He reported that the lesions resolved partially during holidays and weekends and clearly flared in association with his work. There was no history of atopic dermatitis, drug use, or intolerance to metals, rubber, or fruits. On physical examination, linear excoriations with crusts were observed on the dorsa of the left hand, extending to the ventral and dorsal aspects of the forearm, involving the whole area that was in contact with the glove. Lichenified erythematous plaques and excoriations on the dorsal surface of the metacarpophalangeal joints and scaly lesions on the dorsal surfaces of the fingers were also present. On the palm, only discrete hyperkeratosis was seen. The right hand and forearm were free of lesions. He complained of intense pruritus when wearing the rubber glove and admitted to continuous scratching to relieve his discomfort, inducing the linear and excoriated lesions. Treatment with topical corticosteroids was initiated, with progressive resolution of the lesions.