RESUMEN
After large-scale radiation accidents where many individuals are suspected to be exposed to ionizing radiation, biological and physical retrospective dosimetry assays are important tools to aid clinical decision making by categorizing individuals into unexposed/minimally, moderately or highly exposed groups. Quality-controlled inter-laboratory comparisons of simulated accident scenarios are regularly performed in the frame of the European legal association RENEB (Running the European Network of Biological and Physical retrospective Dosimetry) to optimize international networking and emergency readiness in case of large-scale radiation events. In total 33 laboratories from 22 countries around the world participated in the current RENEB inter-laboratory comparison 2021 for the dicentric chromosome assay. Blood was irradiated in vitro with X rays (240 kVp, 13 mA, â¼75 keV, 1 Gy/min) to simulate an acute, homogeneous whole-body exposure. Three blood samples (no. 1: 0 Gy, no. 2: 1.2 Gy, no. 3: 3.5 Gy) were sent to each participant and the task was to culture samples, to prepare slides and to assess radiation doses based on the observed dicentric yields from 50 manually or 150 semi-automatically scored metaphases (triage mode scoring). Approximately two-thirds of the participants applied calibration curves from irradiations with γ rays and about 1/3 from irradiations with X rays with varying energies. The categorization of the samples in clinically relevant groups corresponding to individuals that were unexposed/minimally (0-1 Gy), moderately (1-2 Gy) or highly exposed (>2 Gy) was successfully performed by all participants for sample no. 1 and no. 3 and by ≥74% for sample no. 2. However, while most participants estimated a dose of exactly 0 Gy for the sham-irradiated sample, the precise dose estimates of the samples irradiated with doses >0 Gy were systematically higher than the corresponding reference doses and showed a median deviation of 0.5 Gy (sample no. 2) and 0.95 Gy (sample no. 3) for manual scoring. By converting doses estimated based on γ-ray calibration curves to X-ray doses of a comparable mean photon energy as used in this exercise, the median deviation decreased to 0.27 Gy (sample no. 2) and 0.6 Gy (sample no. 3). The main aim of biological dosimetry in the case of a large-scale event is the categorization of individuals into clinically relevant groups, to aid clinical decision making. This task was successfully performed by all participants for the 0 Gy and 3.5 Gy samples and by 74% (manual scoring) and 80% (semiautomatic scoring) for the 1.2 Gy sample. Due to the accuracy of the dicentric chromosome assay and the high number of participating laboratories, a systematic shift of the dose estimates could be revealed. Differences in radiation quality (X ray vs. γ ray) between the test samples and the applied dose effect curves can partly explain the systematic shift. There might be several additional reasons for the observed bias (e.g., donor effects, transport, experimental conditions or the irradiation setup) and the analysis of these reasons provides great opportunities for future research. The participation of laboratories from countries around the world gave the opportunity to compare the results on an international level.
Asunto(s)
Aberraciones Cromosómicas , Liberación de Radiactividad Peligrosa , Humanos , Estudios Retrospectivos , Radiometría/métodos , Bioensayo/métodos , Cromosomas , Relación Dosis-Respuesta en la RadiaciónRESUMEN
Despite tremendous progress in cell-based therapies for heart repair, many challenges still exist. To enhance the therapeutic potential of cell therapy one approach is the combination of cells with biomaterial delivery vehicles. Here, we developed a biomimetic and biodegradable micro-platform based on polymeric microparticles (MPs) capable of maximizing the therapeutic potential of cardiac progenitor cells (CPCs) and explored its efficacy in a rat model of chronic myocardial infarction. The transplantation of CPCs adhered to MPs within the infarcted myocardial microenvironment improved the long-term engraftment of transplanted cells for up to one month. Furthermore, the enhancement of cardiac cellular retention correlated with an increase in functional recovery. In consonance, better tissue remodeling and vasculogenesis were observed in the animals treated with cells attached to MPs, which presented smaller infarct size, thicker right ventricular free wall, fewer deposition of periostin and greater density of vessels than animals treated with CPCs alone. Finally, we were able to show that part of this beneficial effect was mediated by CPC-derived extracellular vesicles (EVs). Taken together, these findings indicate that the biomimetic microcarriers support stem cell survival and increase cardiac function in chronic myocardial infarction through modulation of cardiac remodeling, vasculogenesis and CPCs-EVs mediated therapeutic effects. The biomimetic microcarriers provide a solution for biomaterial-assisted CPC delivery to the heart. STATEMENT OF SIGNIFICANCE: In this study, we evaluate the possibility of using a biomimetic and biodegradable micro-platform to improve cardiovascular progenitor therapy. The strategy reported herein serves as an injectable scaffold for adherent cells due to their excellent injectability through cardiac catheters, capacity for biomimetic three-dimensional stem cell support and controllable biodegradability. In a rat model of chronic myocardial infarction, the biomimetic microcarriers improved cardiac function, reduced chronic cardiac remodeling and increased vasculogenesis through the paracrine signaling of CPCs. We have also shown that extracellular vesicles derived from CPCs cultured on biomimetic substrates display antifibrotic effects, playing an important role in the therapeutic effects of our tissue-engineered approach. Therefore, biomimetic microcarriers represent a promising and effective strategy for biomaterial-assisted CPC delivery to the heart.
Asunto(s)
Infarto del Miocardio , Remodelación Ventricular , Animales , Biomimética , Células Cultivadas , Infarto del Miocardio/terapia , Miocardio , Miocitos Cardíacos , Ratas , Trasplante de Células MadreRESUMEN
Despite the great advances accomplished in the treatment of pediatric cancers, recurrences and metastases still exacerbate prognosis in some aggressive solid tumors such as neuroblastoma and osteosarcoma. In view of the poor efficacy and toxicity of current chemotherapeutic treatments, we propose a single multitherapeutic nanotechnology-based strategy by co-assembling in the same nanodevice two amphiphilic antitumor agents: squalenoyl-gemcitabine and edelfosine. Homogeneous batches of nanoassemblies were easily formulated by the nanoprecipitation method. Their anticancer activity was tested in pediatric cancer cell lines and pharmacokinetic studies were performed in mice. In vitro assays revealed a synergistic effect when gemcitabine was co-administered with edelfosine. Squalenoyl-gemcitabine/edelfosine nanoassemblies were found to be capable of intracellular translocation in patient-derived metastatic pediatric osteosarcoma cells and showed a better antitumor profile than squalenoyl-gemcitabine nanoassemblies alone. The intravenous administration of this combinatorial nanomedicine in mice exhibited a controlled release behavior of gemcitabine and diminished edelfosine plasma peak concentrations. These findings make it a suitable pre-clinical candidate for childhood cancer therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Óseas/tratamiento farmacológico , Nanoconjugados/uso terapéutico , Nanopartículas , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Éteres Fosfolípidos/farmacología , Escualeno/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Sinergismo Farmacológico , Femenino , Concentración 50 Inhibidora , Inyecciones Intravenosas , Ratones Desnudos , Nanoconjugados/administración & dosificación , Nanoconjugados/química , Neuroblastoma/metabolismo , Neuroblastoma/patología , Osteosarcoma/metabolismo , Osteosarcoma/patología , Éteres Fosfolípidos/administración & dosificación , Éteres Fosfolípidos/química , Éteres Fosfolípidos/farmacocinética , Escualeno/administración & dosificación , Escualeno/química , Escualeno/farmacocinética , Escualeno/uso terapéuticoRESUMEN
The development and use of nanomaterials are increasing significantly. Among nanomaterials, carbon nanotubes are of particular interest due to its distinctive physicochemical properties. This material composed of sheets of graphite has very high thermal conductivity, metallic-type electrical conductivity, stiffness, toughness and unique ability to bond to itself in an extended network with extraordinary strength. Its application in the industry is continuously growing, which could lead to the accumulation in the environment and a consequent impact on both humans and ecosystems. Considering that environmental systems are dynamic, it is difficult to predict the risks associated with the release of nanomaterials to the environment. Bioindicators are useful tools as primary signals of environmental risk, and their responses reveal the organism and ecosystem health. In the present study, we evaluated the impact of multi-walled carbon nanotubes with different dimensions and agglomeration pattern on zebrafish embryo and larvae; mainly, studies were focused on physiological and behavioral responses. In embryos, measurements were hatching rate, morphology changes, and viability. In larvae, locomotor activity, heart rate, innate inflammatory response, general and tissue-specific morphology were measured. MWCNT-S (short, wide and mostly dispersed) caused depression of the locomotor activity of larvae, indicating an alteration of the central nervous system, and depression of neutrophil migration activity. MWCNT-L (long, thin and agglomerated) caused malformations during larval development, a decrease of neutrophil migration and alteration of cardiac rhythm. Results obtained for both carbon nanotubes were different, highlighting the importance of dimensions of the same nanomaterial, and also the kind of agglomeration and shape adopted, for the toxic effects on organisms.
RESUMEN
Among anticancer nanomedicines, squalenoyl nanocomposites have obtained encouraging outcomes in a great variety of tumors. The prodrug squalenoyl-gemcitabine has been chosen in this study to construct a novel multidrug nanosystem in combination with edelfosine, an alkyl-lysophopholipid with proven anticancer activity. Given their amphiphilic nature, it was hypothesized that both anticancer compounds, with complementary molecular targets, could lead to the formation of a new multitherapy nanomedicine. Nanoassemblies were formulated by the nanoprecipitation method and characterized by dynamic light scattering, transmission electron microscopy and X-ray photoelectron spectroscopy. Because free edelfosine is highly hemolytic, hemolysis experiments were performed using human blood erythrocytes and nanoassemblies efficacy was evaluated in a patient-derived metastatic pediatric osteosarcoma cell line. It was observed that these molecules spontaneously self-assembled as stable and monodisperse nanoassemblies of 51⯱â¯1â¯nm in a surfactant/polymer free-aqueous suspension. Compared to squalenoyl-gemcitabine nanoassemblies, the combination of squalenoyl-gemcitabine with edelfosine resulted in smaller particle size and a new supramolecular conformation, with higher stability and drug content, and ameliorated antitumor profile.
Asunto(s)
Desoxicitidina/análogos & derivados , Lisofosfolípidos/química , Éteres Fosfolípidos/química , Profármacos/química , Escualeno/química , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Desoxicitidina/química , Humanos , Microscopía Electrónica de Transmisión/métodos , Nanomedicina/métodos , Tamaño de la Partícula , GemcitabinaRESUMEN
INTRODUCTION: Transforming growth factor beta-1 (TGF-ß1) is a pleiotropic cytokine. Its relationship with atherosclerosis is debatable, protective or deleterious effects have been described. Alcoholics are at increased vascular risk. Although TGF-ß1 is increased in alcoholics, its role on vascular risk factors has not been analyzed. This is the objective of this study. PATIENTS AND METHODS: 79 heavy alcoholics and 34 controls were included. Calcium deposition in the aortic arch was assessed in the plain thorax X-ray film. Ankle-brachial index was recorded in 48 patients. All the patients underwent complete laboratory evaluation, including serum levels of TGF-ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, and interferon-γ (IFN-γ).We analyzed the relationships between TGF-ß1 and vascular risk factors by both univariate (parametric or non parametric tests), or multivariate analysis to discern on which variables TGF-ß1 levels depend. RESULTS: Serum TGF-ß1 levels were higher among patients (t = 2.73; P = 0.008), but no differences exist among cirrhotics (17246 ± 11,021 pg/mL) and non-cirrhotics (21,340 ± 12,442 pg/mL). TGF-ß1 showed significant correlations with total cholesterol (r = 0.28; P = 0.017) and HDL- cholesterol (r = 0.25; P = 0.042), and inverse correlations with body mass index (BMI; ρ = -0.37; P = 0.004), IL-4 (ρ = -0.31; P = 0.009), INF-γ (ρ = -0.28; P = 0.001), and IL-6 (ρ = -0.38; P = 0.001). By multivariate analysis, only BMI, IL-6 and HDL-cholesterol showed independent relationships with TGF-ß1. No relationships were observed with ankle-brachial index or calcium in the aortic arch, hypertension, diabetes, left ventricular hypertrophy or atrial fibrillation. CONCLUSION: TGF-ß1 levels are increased in alcoholics, but are unrelated to vessel wall calcification or arterial stiffness.
Asunto(s)
Alcohólicos , Alcoholismo/sangre , Factor de Crecimiento Transformador beta1/sangre , Calcificación Vascular/sangre , Rigidez Vascular/fisiología , Anciano , Alcoholismo/diagnóstico , Alcoholismo/epidemiología , Aorta Torácica/metabolismo , Aorta Torácica/patología , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Calcificación Vascular/diagnóstico , Calcificación Vascular/epidemiologíaRESUMEN
Neuregulin-1 loaded poly(lactic-co-glycolic acid) (PLGA) microparticles hold great promise for treating acute myocardial infarction, as they have been proved to recover heart function and induce positive heart remodelling in preclinical studies. More recently, the inflammatory response of the heart after acute myocardial infarction (AMI) has been identified as one of the major mechanisms in cardiac tissue remodelling and repair. However, the connection between neuregulin-1 PLGA microparticles and inflammation is still not well characterised. In the present study we assessed this relationship in a mouse AMI model. First, in vitro evidence indicated that neuregulin-1 PLGA microparticles induced a macrophage polarisation toward a regenerative phenotype (CD206+ cells), preventing macrophages from evolving toward the inflammatory phenotype (B7-2+ cells). This correlated with in vivo experiments, where neuregulin-1 PLGA microparticles locally improved the CD206+/B7-2+ ratio. Moreover, neuregulin-1 PLGA microparticles were administered at different time points (15 min, 24, 72 and 168 h) after infarction induction without causing secondary inflammatory issues. The time of treatment administration did not alter the inflammatory response. Taken together, these results suggest that neuregulin-1 PLGA microparticles can be administered depending on the therapeutic window of the encapsulated drug and that they enhance the heart's reparative inflammatory response after acute myocardial infarction, helping cardiac tissue repair.
Asunto(s)
Portadores de Fármacos/química , Corazón/fisiología , Macrófagos/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Neurregulina-1/uso terapéutico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Regeneración , Animales , Línea Celular , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Corazón/fisiopatología , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Neurregulina-1/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéuticoRESUMEN
Due to their high porosity and versatile composition and structure, nanoscaled Metal-Organic Frameworks (nanoMOFs) have been recently proposed as novel drug delivery systems, and have been demonstrated to have important capacities and potential for controlled release of different active ingredients. Gentamicin (GM; a broad spectrum aminoglycoside antibiotic indicated in bacterial septicemia therapy) has great therapeutic interest, but the associated bioavailability and toxicity drawbacks accompanying high doses and repeated administration of this free drug make its encapsulation inside new nanocarriers necessary. GM encapsulation within two different porous biofriendly Fe and Zr-carboxylates nanoMOFs was performed by a simple impregnation method, with full characterization of the resulting GM-containing solid using a large panel of techniques (X ray powder diffraction-XRPD, Fourier transform infrared spectroscopy-FTIR, thermogravimetric analysis-TGA, N2 sorption, scanning electron microscopy-SEM, dynamic light scattering-DLS, ζ-potential, fluorescence spectroscopy and molecular simulations). High reproducible encapsulation rates, reaching 600⯵g of GM per·mg of formulation, were obtained using the biocompatible mesoporous iron(III) trimesate nanoparticles (NPs) MIL-100(Fe) (MIL: Materials from Institut Lavoisier). In vitro GM delivery studies were also carried out using different oral and intravenous simulated physiological conditions, with complete antibiotic release within 8â¯h when using protein free media, but lower release rates in the presence of proteins. Furthermore, in vitro toxicity of GM-containing MIL-100(Fe) NPs was investigated on two different cell lines: a monocyte from leukemia (THP-1) and adherent fibroblastoid cells (NIH/3T3). These nanoMOFs had a low cytotoxic profile with IC50 values up to 1â¯mg·mL-1, ensuring adequate cell proliferation after 24â¯h. Finally, antibacterial activity studies were carried out on two Gram-positive bacteria and one Gram-negative bacterium: S. aureus, S. epidermidis and P. aeruginosa, respectively. GM-loaded MIL-100(Fe) NPs exhibited the same activity as free GM, confirming that the antibiotic activity of the released GM was conserved.
Asunto(s)
Antibacterianos/administración & dosificación , Sistemas de Liberación de Medicamentos , Gentamicinas/administración & dosificación , Nanopartículas del Metal , Animales , Antibacterianos/farmacología , Antibacterianos/toxicidad , Preparaciones de Acción Retardada , Gentamicinas/farmacología , Gentamicinas/toxicidad , Humanos , Concentración 50 Inhibidora , Hierro/química , Estructuras Metalorgánicas/química , Ratones , Pruebas de Sensibilidad Microbiana , Células 3T3 NIH , Porosidad , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Células THP-1 , Pruebas de Toxicidad/métodos , Circonio/químicaRESUMEN
Epilepsy is a neurological disorder treated with antiepileptic drugs (AEDs). Since AEDs are administered in women in childbearing age, it is critical to study if drugs are capable of inducing developmental toxicity. Along the bibliography available, there is no research comparing teratogenicity and anticonvulsant effect within the same study. In the present study, we evaluated the teratogenic and anticonvulsant effects of six different AEDs: carbamazepine, levetiracetam, lamotrigine, phenobarbital, phenytoin and valproic acid. Zebrafish was the selected animal model because of its small size, rapid external development and similar neurophysiology to mammals. Zebrafish embryo and larvae were exposed to AEDs. Embryo development was monitored by their hatching and morphology. In larvae, locomotor activity was measured as a parameter of neurotoxicity. Finally, anticonvulsant effect was determined after exposure to AEDs in zebrafish larvae treated with the proconvulsant drug pentylenetetrazole. Our results suggest that lamotrigine and phenytoin could be suitable non-teratogenic and efficient anticonvulsant options for epilepsy treatment.
Asunto(s)
Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Larva/efectos de los fármacos , Teratogénesis/efectos de los fármacos , Pez Cebra/embriología , Animales , Anticonvulsivantes/toxicidad , Evaluación Preclínica de MedicamentosRESUMEN
In recent years, the use of commercial nanoparticles in different industry and health fields has increased exponentially. However, the uncontrolled application of nanoparticles might present a potential risk to the environment and health. Toxicity of these nanoparticles is usually evaluated by a fast screening assay in zebrafish (Danio rerio). The use of this vertebrate animal model has grown due to its small size, great adaptability, high fertilization rate and fast external development of transparent embryos. In this review, we describe the toxicity of different micro- and nanoparticles (carbon nanotubes, dendrimers, emulsions, liposomes, metal nanoparticles, and solid lipid nanoparticles) associated to their biophysical properties using this model. The main biophysical properties studied are size, charge and surface potential due to their impact on the environment and health effects. The review also discusses the correlation of the effects of the different nanoparticles on zebrafish. Special focus is made on morphological abnormalities, altered development and abnormal behavior. The last part of the review debates changes that should be made in future directions in order to improve the use of the zebrafish model to assess nanotoxicity.
RESUMEN
Cancer is a leading cause of mortality in the world, with osteosarcoma being one of the most common types among children between 1 and 14 years old. Current treatments including preoperative chemotherapy, surgery and postoperative chemotherapy produce several side effects with limited effectiveness. The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment. However, in vitro validation of these vehicles is limited due to fluid stagnation in current techniques, in which nanoparticles sediment onto the bottom of the wells killing the cells by asphyxiation. In the current series of experiments, results obtained with methotrexate-lipid nanoparticles under dynamic assay conditions are presented as a promising alternative to current free drug based therapies. Effects on the viability of the U-2 OS osteosarcoma cell line of recirculation of cell media, free methotrexate and blank and methotrexate containing lipid nanoparticles in a 11 µM concentration were successfully assessed. In addition, several designs for the microfluidic platform used were simulated using COMSOL-Multiphysics, optimized devices were fabricated using soft-lithography and simulated parameters were experimentally validated. Nanoparticles did not sediment to the bottom of the platform, demonstrating the effectiveness of the proposed system. Moreover, encapsulated methotrexate was the most effective treatment, as after 72 h the cell population was reduced nearly 40% while under free methotrexate circulation the cell population doubled. Overall, these results indicate that methotrexate-lipid nanoparticles are a promising targeted therapy for osteosarcoma treatment.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Metotrexato/química , Metotrexato/farmacología , Nanoestructuras/química , Osteosarcoma/patología , Cápsulas , Línea Celular Tumoral , Portadores de Fármacos/química , Humanos , Dispositivos Laboratorio en un Chip , Lípidos/químicaRESUMEN
Polo like kinase 2 (PLK2), a serine/threonine serum inducible kinase, has been proposed to be the major factor responsible for phosphorylating alpha-synuclein (α-syn) at Serine-129 (Ser-129) in Parkinson's disease (PD). A suitable strategy to gain insights into PLK2's biological effects might be to increase PLK2 intracellular levels with the aim of reproducing the slow progressive neuronal changes that occur in PD. The goal of this study was to develop and characterize a novel drug delivery system (DDS) for PLK2 cytosolic delivery using Total recirculating one machine system (TROMS), a technique capable of encapsulating fragile molecules while maintaining their native properties. A protocol for nanoparticle (NP) preparation using TROMS was set up. NPs showed a mean diameter of 257±15.61nm and zeta potential of -16±2mV, suitable for cell internalization. TEM and SEM images showed individual, spherical, dispersed NPs. The drug entrapment efficacy was 61.86±3.9%. PLK2-NPs were able to enter SH-SY5Y cells and phosphorylate α-syn at Ser-129, demonstrating that the enzyme retained its activity after the NP manufacturing process. This is the first study to develop a DDS for continuous intracellular delivery of PLK2. These promising results indicate that this novel nanotechnology approach could be used to elucidate the biological effects of PLK2 on dopaminergic neurons.
Asunto(s)
Nanopartículas/química , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/química , Serina/metabolismo , alfa-Sinucleína/metabolismo , Línea Celular , Neuronas Dopaminérgicas/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Nanopartículas/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/farmacologíaRESUMEN
The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/fisiopatología , Sistemas de Liberación de Medicamentos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , alfa-Sinucleína/metabolismo , Antioxidantes/administración & dosificación , Dopamina/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Terapia Genética , Humanos , Cuerpos de Lewy/metabolismo , Lisosomas/metabolismo , Mitocondrias/fisiología , Factores de Crecimiento Nervioso/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo , Péptidos/administración & dosificación , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term (12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials.
Asunto(s)
Fármacos Cardiovasculares/farmacocinética , Portadores de Fármacos , Ácido Láctico/química , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Neurregulina-1/farmacocinética , Poliésteres/química , Polietilenglicoles/química , Ácido Poliglicólico/química , Animales , Disponibilidad Biológica , Biotinilación , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/química , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Composición de Medicamentos , Estabilidad de Medicamentos , Femenino , Humanos , Macrófagos/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Miocardio/patología , Neurregulina-1/administración & dosificación , Neurregulina-1/química , Tamaño de la Partícula , Fagocitosis , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas Sprague-Dawley , Receptor ErbB-4/efectos de los fármacos , Receptor ErbB-4/metabolismo , Proteínas Recombinantes/farmacocinéticaRESUMEN
Protein phosphatase 2A (PP2A) is a serin-threonin phosphatase that regulates many proteins critical for malignant cell behavior; therefore, PP2A is considered to be a human tumor suppressor. In this study, we assessed the pharmacokinetic profile and the antileukemic effects of the PP2A activator FTY720, free or encapsulated in lipid nanoparticles, in in vitro and in vivo models of acute myeloid leukemia. FTY720 lipid nanoparticles presented diameters around 210 nm, with an encapsulation efficiency up to 75% and significantly increased FTY720 oral bioavailability. In addition, FTY720 restores PP2A phosphatase activity and decreases phosphorylation of PP2A and its targets Akt, ERK1/2 and STAT5, all implicated in the pathogenesis of acute myeloid leukemia. Moreover, FTY720 exerts an additive anti-leukemic effect in combination with drugs used in standard induction therapy. Importantly, FTY720 lipid nanoparticles were more efficient at inducing cell growth arrest and apoptosis than FTY720 solution. Finally, oral administration of FTY720 lipid nanoparticles to mice every three days was as effective in reducing acute myeloid leukemia xenograft tumor growth as daily oral administration of FTY720. These results provide the first evidence for the potential use of FTY720 lipid nanoparticles as an oral therapeutic agent in acute myeloid leukemia.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Leucemia Mieloide Aguda/tratamiento farmacológico , Lípidos/química , Nanopartículas/química , Glicoles de Propileno/administración & dosificación , Esfingosina/análogos & derivados , Animales , Antineoplásicos/química , Apoptosis , Caspasas/metabolismo , Proliferación Celular , Citarabina/administración & dosificación , Activación Enzimática , Femenino , Clorhidrato de Fingolimod , Células HL-60 , Humanos , Idarrubicina/administración & dosificación , Ratones , Ratones Transgénicos , Nanotecnología , Esfingosina/administración & dosificaciónRESUMEN
Myocardial infarction causes almost 7.3 million deaths each year worldwide. However, current treatments are more palliative than curative. Presently, cell and protein therapies are considered the most promising alternative treatments. Clinical trials performed until now have demonstrated that these therapies are limited by protein short half-life and by low transplanted cell survival rate, prompting the development of novel cell and protein delivery systems able to overcome such limitations. In this review we discuss the advances made in the last 10years in the emerging field of cardiac repair using biomaterial-based delivery systems with focus on the progress made on preclinical in vivo studies. Then, we focus in cardiac tissue engineering approaches, and how the incorporation of both cells and proteins together into biomaterials has opened new horizons in the myocardial infarction treatment. Finally, the ongoing challenges and the perspectives for future work in cardiac tissue engineering will also be discussed.
Asunto(s)
Materiales Biocompatibles/química , Corazón/fisiología , Infarto del Miocardio/terapia , Regeneración , Medicina Regenerativa/métodos , Ingeniería de Tejidos/métodos , Animales , Materiales Biocompatibles/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Ensayos Clínicos como Asunto , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Humanos , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Infarto del Miocardio/patología , Miocardio/patología , Andamios del Tejido/químicaRESUMEN
INTRODUCTION: The specific diagnosis of toxic encephalopathy (TE) by chronic exposure to neurotoxics presents difficulties, mainly due to lack of consensus of clinical diagnostic criteria. The EUROQUEST (EQ) is a multicultural tool proposed for using in epidemiological studies on neurotoxicity. The aim of this study was to validate the Spanish version of this questionnaire for using as a diagnostic and prevention tool in the workplace. METHODS: After translation and cultural adaptation, leading to a final questionnaire in Spanish, validation was performed by asking a total of 759 people to complete the questionnaire, of whom 292 were workers exposed to neurotoxic solvents, 391 non-exposed workers, and 22 patients diagnosed with chronic alcoholism. RESULTS: In the analysis of the reliability, the Cronbach α value for the questionnaire was 0.94, indicating very high internal consistency. The test-retest reproducibility analysis was highly significant (r=0.91, P<.001). In the analysis of the validity, comparing the three study groups, the mean scores of the questions included in each of the dimensions of the test (ANOVA) detected major differences in the dimensions that assess cognitive symptoms, depressive disorders, sleep and psychopathological symptoms. After factor analysis obtained a total of nine axes, allowing a clear distinction between the three study groups.
Asunto(s)
Síndromes de Neurotoxicidad/diagnóstico , Pruebas Psicológicas , Encuestas y Cuestionarios , Traducciones , Adulto , Análisis de Varianza , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes de Neurotoxicidad/prevención & control , Exposición Profesional , Reproducibilidad de los Resultados , Medición de Riesgo , EspañaRESUMEN
Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.
Asunto(s)
Bioensayo/métodos , Planificación en Desastres/organización & administración , Traumatismos por Radiación/prevención & control , Monitoreo de Radiación/métodos , Protección Radiológica/métodos , Liberación de Radiactividad Peligrosa/prevención & control , Urgencias Médicas , Europa (Continente) , Humanos , Exposición a la Radiación/prevención & control , Administración de la Seguridad/organización & administraciónAsunto(s)
Chaperonas de Histonas/fisiología , Leucemia Mieloide Aguda/tratamiento farmacológico , Glicoles de Propileno/farmacología , Proteína Fosfatasa 2/antagonistas & inhibidores , Esfingosina/análogos & derivados , Factores de Transcripción/fisiología , Línea Celular Tumoral , Proteínas de Unión al ADN , Clorhidrato de Fingolimod , Humanos , Leucemia Mieloide Aguda/enzimología , Péptidos/farmacología , Esfingosina/farmacologíaRESUMEN
Myocardial infarction (MI) is the leading cause of death worldwide, and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose-derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58 ± 3.84%. NRG maintained its biological activity after the microencapsulation process. ADSCs adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue 2 weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach.