Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection.

Intranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)-lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding [immunoglobulin G (IgG) and IgA] and neutralizing antibodies. Intranasally vaccinated hamsters also had decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. Together, this study demonstrates successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.

Self-assembled hyaluronan nanocapsules for the intracellular delivery of anticancer drugs.

Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of -20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery.

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness.

PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

A novel low molecular weight nanocomposite hydrogel formulation for intra-tumoural delivery of anti-cancer drugs.

Herein, an injectable formulation composed of a low molecular weight gelator (LMWG) based hydrogel and drug-loaded polymeric nanocapsules (NCs) is described. The NCs, made of hyaluronic acid and polyglutamic acid and loaded with C14-Gemcitabine (GEM C14), showed a size of 40 and 80 nm and a encapsulation efficiency >90%. These NCs exhibited a capacity to control the release of the encapsulated drug for >1 month. GEM C14-loaded NCs showed activity against various cancer cell lines in vitro; cell growth inhibition by 50% (GI50) values of 15 ±â€¯6, 10 ±â€¯9, 13 ±â€¯3 and 410 ±â€¯463 nM were obtained in HCT 116, MIA PaCa-2, Panc-1 and Panc-1 GEM resistant cell lines respectively. Nanocomposite hydrogels were prepared using the LMWG - N4-octanoyl-2'-deoxycytidine and loaded for the first time with polymeric NCs. 2% and 4% w/v nanocapsule concentrations as compared to 8% w/v NC concentrations with 2% and 3% w/v gelator concentrations gave mechanically stronger gels as determined by oscillatory rheology. Most importantly, the nanocomposite formulation reformed instantly into a gel after injection through a needle. Based on these properties, the nanocomposite gel formulation has potential for the intratumoural delivery of anticancer drugs.

Valor pronóstico de las evaluaciones del crecimiento cerebelar y de los movimientos generales para el neurodesarrollo del gran prematuro entre los 18 y 24 meses de edad corregida / Predictive value of cerebellar growth and general movements assessments for neurodevelopment of very preterm infants at 18-24 months’ corrected age

Introducción. La evaluación de los movimientos de ajetreo es sumamente sensible a la hora de predecir el desenlace a largo plazo o la parálisis cerebral del neonato prematuro, un tipo de paciente en el que se ha descrito el crecimiento anómalo del cerebelo. Objetivo. Comparar el valor pronóstico de la determinación ecográfica del crecimiento anómalo del cerebelo y el de la evaluación de los movimientos de ajetreo en el neurodesarrollo de grandes prematuros a los 18-24 meses de edad corregida. Sujetos y métodos. Estudio prospectivo con una cohorte de 88 neonatos (32 semanas o menos de gestación) en que se analizó el diámetro transversal del cerebelo por medio de una ecografía semanal hasta las 40 semanas de edad corregida. Los movimientos de ajetreo se evaluaron a los tres meses de edad corregida. El estado de maduración neurológica a los 18-24 meses de edad corregida se evaluó en 68 neonatos con la escala de evaluación de las competencias en el desarrollo infantil (SGS-II) y la escala de evaluación neurológica de Amiel-Tison (ATNA). Resultados. En la edad a término, el crecimiento del cerebelo fue inferior al tercer percentil en 11 neonatos (10,3%). Los movimientos de ajetreo eran normales en 42 (61,8%), y anormales o ausentes, en 7 (10,3%). A los 18-24 meses de edad corregida, 54 (79,4%) mostraron resultados normales en la SGS-II y 6 (8,8%) fueron calificados como afectados por parálisis cerebral según la ATNA. El diámetro cerebelar inferior al tercer percentil a término estuvo asociado con un desenlace motor anómalo y los movimientos de ajetreo normales se correlacionaron con el neurodesarrollo normal. Conclusión. La estimación del tamaño del cerebelo y las exploraciones funcionales (movimientos de ajetreo) poseen un importante papel complementario en el pronóstico del desarrollo nervioso en el gran prematuro (AU)

Introduction. Fidgety movements assessments is very sensitive predicting long-term outcome or cerebral palsy of preterm, disrupted cerebellar growth has been reported in these patients. Aim. To compare the predictive value of cerebellar ultrasound growth and fidgety movements assessments, for neurodevelopment outcome of very preterm at 18-24 month’s corrected age (CA). Subjects and methods. Prospective study of 88 infants cohort (≤ 32 weeks’ gestation), transverse cerebellar diameter was obtained by ultrasound via mastoid fontanel, in a weekly basis, until 40 weeks CA. Fidgety movements were assessed at 3 months CA. Neurodevelopment outcome at 18-24 month’s CA was evaluated in 68 using Schedule of Growing Skills II Scale (SGS-II) and Amiel-Tison Neurologic Assessment (ATNA). Results. At term age, cerebellar growth was under 3rd percentile in 11 (10.3%). Fidgety movements were normal in 42 (61.8%) and abnormal or absent in 7 (10.3%). At 18-24 months CA, 54 (79.4%) were normal by the SGS-II and in 6 (8.8%) ATNA classified as cerebral palsy. Cerebellar diameter under 3rd percentile at term was associated with abnormal motor outcome and normal fidgety movements correlated with normal neurodevelopment. Conclusion. Ultrasound cerebellar measurements and functional examinations (fidgety movements) have important complementary roles in predicting neurodevelopment of very preterm (AU)

Targeting cancer with hyaluronic acid-based nanocarriers: recent advances and translational perspectives.

Hyaluronic acid is a natural polysaccharide that has been widely explored for the development of anticancer therapies due to its ability to target cancer cells. Moreover, advances made in the last decade have revealed the versatility of this biomaterial in the design of multifunctional carriers, intended for the delivery of a variety of bioactive molecules, including polynucleotides, immunomodulatory drugs and imaging agents. In this review, we aim to provide an overview of the major recent achievements in this field, highlighting the application of the newly developed nanostructures in combination therapies, immunomodulation and theranostics. Finally, we will discuss the main challenges and technological advances that will allow these carriers to be considered as candidates for clinical development.

Development of a novel mucosal vaccine against strangles by supercritical enhanced atomization spray-drying of Streptococcus equi extracts and evaluation in a mouse model.

Strangles is an extremely contagious and sometimes deadly disease of the Equidae. The development of an effective vaccine should constitute an important asset to eradicate this worldwide infectious disease. In this work, we address the development of a mucosal vaccine by using a Supercritical Enhanced Atomization (SEA) spray-drying technique. Aqueous solutions containing the Streptococcus equi extracts and chitosan were converted into nanospheres with no use of organic solvents. The immune response in a mouse model showed that the nanospheres induced a well-balanced Th1 and Th2 response characterized by a unitary ratio between the concentrations of IgG2a and IgG1, together with IgA production. This strategy revealed to be an effective alternative for immunization against S. equi, and therefore, it may constitute a feasible option for production of a strangles vaccine.