Influence of magnetic nanoparticle degradation in the frame of magnetic hyperthermia and photothermal treatments

This work aims at studying how the transformations that magnetic nanoparticles suffer in vivo affect their heating properties in the frame of hyperthermia treatments. Iron oxide magnetic nanoparticles (≈13 nm) with two different coatings [PMAO (polymaleic anhydride-alt-1-octadecene) and DMSA (dimercaptosuccinic acid)] have been subjected to an accelerated degradation in a medium simulating lysosome conditions. The particles physicochemical properties (size, size distribution, and magnetic properties) have been followed over the degradation process along 24 days. It was found that DMSA-coated particles degraded much faster than PMAO-coated ones. In addition, their heating properties under both the exposure to an alternating magnetic field or a near infrared light have been tracked along this degradation processes, assessing how the changes in their physicochemical properties affect their heating capacity. Along the degradation procedure, a stronger decrease of the particles heating properties has been observed in the frame of magnetic hyperthermia measurements, in comparison with the photothermal ones. Finally, the PMAO-coated particles have been selected for a degradation study in vivo after intratumoral administration. Interestingly, although the number of particles decreases with time in the tissue, the size and size distribution of the particles do not change significantly over time. This work is especially relevant in the frame of the design of in vivo hyperthermia treatments using magnetic nanoparticles as it would provide fundamental clues regarding the need of repeated doses or the possible use of a single administration depending on the treatment duration

Surco en cabeza femoral como signo de inestabilidad de cadera en pacientes con Síndrome de Down.

La inestabilidad de cadera en pacientes afectos de síndrome de Down es una entidad poco frecuente, en la actualidad todavía existe controversia sobre las anomalías anatómicas asociadas. El objetivo de este trabajo es describir los cambios anatómicos en las caderas de pacientes con inestabilidad en el síndrome de Down (SD). Hemos revisado las tomografías computarizadas (TC) de los pacientes afectos de luxación de cadera con SD. A tres de los 7 pacientes intervenidos en nuestro centro, se les había realizado TC de caderas. En todas las TC mostraban la presen - cia de lesión lineal vertical (surco) localizada en región epifisaria, atravesando la fisis, de localización antero-interna. Creemos que la posición adoptada cuando duermen (flexión, aducto y rotación interna) puede producir hiperpresión de la cabeza femoral sobre la ceja acetabular posterior, produciendo un surco vertical. La presencia de esta lesión puede ser sugestiva de inestabilidad subclínica de cadera en ausencia de episodio de luxación.Hip instability in patients with Down syndrome is a rare entity, currently there is still controversy about the associated anatomical anomalies. The aim of the study is to describe the anatomical changes in the hips of patients with instability in Down syndrome (DS). We have reviewed the computed tomography (CT) of patients with hip dislocation with SD. Three of the 7 patients treated in our center are performed CT had hips. All CT showed the presence of vertical linear lesion (groove) located in epiphyseal region, crossing the physis, antero-internal location. We believe that the position taken when sleeping (flexion, adduction and internal rotation) can produce overpressure of the femoral head over the posterior acetabular rim, producing a vertical groove. The presence of this lesion can be suggestive of subclinical instability in the absence of hip dislocation

Hipertermia magnética basada en nanopartículas de óxido de hierro como terapia antitumoral: del cultivo celular tridimensional al modelo in vivo

La hipertermia magnética es una terapia prometedora para el tratamiento localizado del cáncer. Bajo la exposición a un campo magnético alterno externo, las nanopartículas magnéticas actúan como agentes de calentamiento que inducen la muerte celular en la región tratada. La comprensión de los mecanismos moleculares implicados en el daño celular generado por este tratamiento es crucial para la aplicación exitosa de esta terapia. Para esta tesis, se prepararon nanopartículas magnéticas esféricas de 11 nm por el método de descomposición térmica, que posteriormente se recubrieron con PMAO (poli (anhídrido maleico-alt-1-octadeceno) y finalmente se funcionalizaron con glucosa. Con el objetivo de evaluar la influencia de la localización de las nanopartículas en la eficacia del tratamiento térmico, se prepararon diferentes modelos de cultivo celular tridimensional (3D) basados en geles de colágeno, tanto en la línea celular de macrófagos murinos, RAW264.7, como en la línea de células tumorales pancreáticas humanas, MIAPaca-2. En un modelo, todas las partículas se encontraban localizadas dentro de las células (Modelo In), mientras que el otro modelo, contenía partículas tanto dentro como fuera de las células (Modelo In&Out). Además, se desarrolló un modelo murino de xenoinjerto de cáncer pancreático humano basado en las células MIAPaca-2. La internalización de las nanopartículas magnéticas, así como los mecanismos de muerte celular inducidos por diferentes condiciones de tratamiento de hipertermia se evaluaron por microscopía confocal, estudios de citometría de flujo, ensayos de biología molecular, análisis histológicos, medidas magnéticas y otras técnicas de caracterización analítica. Además, se evaluó el efecto del calentamiento intracelular inducido por las nanopartículas bajo acción del campo magnético mediante simulaciones computacionales. En general, los resultados in vitro e in vivo obtenidos en esta tesis han demostrado que la terapia térmica con hipertermia magnética tiene un importante efecto en la modulación de la matriz extracelular, así como en la inducción de mecanismos de inmuno-estimulación. Fenómeno especialmente relevante en la búsqueda de nuevas estrategias terapéuticas para el tratamiento del cáncer de páncreas. Además, las evidencias experimentales de este trabajo demostraron que las vías de muerte celular inducidas por el tratamiento con hipertermia magnética dependen del número de partículas localizadas en el interior de las células. Esto es importante para comprender los mecanismos moleculares que median la respuesta celular a esta terapia térmica. Magnetic hyperthermia is a promising therapy for the localized treatment of cancer. Under the exposure to an external alternating magnetic field, magnetic nanoparticles act as heating agents inducing cell death in the treated region. Understanding the molecular mechanisms involved in the cellular damage generated by this treatment is crucial for the successful application of this therapy. In this thesis, 11 nm spherical magnetic nanoparticles were prepared by thermal decomposition, coated with PMAO (poly (maleic anhydride-alt-1-octadecene) and functionalized with glucose. In order to evaluate the influence of the nanoparticle location in the treatment efficacy, two different three-dimensional (3D) cell culture models, based on collagen gels, were prepared both in the murine macrophage cell line, RAW264.7, as in the human pancreatic tumor cell line, MIAPaca-2. One model kept all the particles inside the cells (In Model) while the other model had particles both inside and outside the cells (In&Out Model). In addition, the xenograft murine model of human pancreatic cancer based in the MIAPaca-2 cells was developed. The magnetic nanoparticle uptake and cell death mechanisms induced by different conditions of the hyperthermia treatment were evaluated by confocal microscopy, flow cytometry studies, molecular biology assays, histological analysis, magnetic measurements and other analytical characterization techniques. In addition, computational simulations to evaluate the intracellular heating effects were also performed. In general, the in vitro and in vivo results obtained in this thesis, showed that magnetic hyperthermia had an important effect in the modulation of the extracellular matrix, as well as in the induction of immune-stimulation mechanisms. Phenomenon especially relevant in the search for new therapeutic strategies for pancreatic cancer. Moreover, the experimental results of this thesis showed that the type of cell death pathways triggered by the magnetic hyperthermia treatment depend on the number of intracellular nanoparticles. This is important in the understanding the molecular mechanisms that mediate the cellular response to this thermal therapy.<br /

Triggering antitumoural drug release and gene expression by magnetic hyperthermia

Magnetic nanoparticles (MNPs) are promising tools for a wide array of biomedical applications. One of their most outstanding properties is the ability to generate heat when exposed to alternating magnetic fields, usually exploited in magnetic hyperthermia therapy of cancer. In this contribution, we provide a critical review of the use of MNPs and magnetic hyperthermia as drug release and gene expression triggers for cancer therapy. Several strategies for the release of chemotherapeutic drugs from thermo-responsive matrices are discussed, providing representative examples of their application at different levels (from proof of concept to in vivo applications). The potential of magnetic hyperthermia to promote in situ expression of therapeutic genes using vectors that contain heat-responsive promoters is also reviewed in the context of cancer gene therapy

Understanding the Influence of a Bifunctional Polyethylene Glycol Derivative in Protein Corona Formation around Iron Oxide Nanoparticles

Superparamagnetic iron oxide nanoparticles are one of the most prominent agents used in theranostic applications, with MRI imaging the main application assessed. The biomolecular interface formed on the surface of a nanoparticle in a biological medium determines its behaviour in vitro and in vivo. In this study, we have compared the formation of the protein corona on highly monodisperse iron oxide nanoparticles with two different coatings, dimercaptosuccinic acid (DMSA), and after conjugation, with a bifunctional polyethylene glycol (PEG)-derived molecule (2000 Da) in the presence of Wistar rat plasma. The protein fingerprints around the nanoparticles were analysed in an extensive proteomic study. The results presented in this work indicate that the composition of the protein corona is very difficult to predict. Proteins from different functional categories—cell components, lipoproteins, complement, coagulation, immunoglobulins, enzymes and transport proteins—were identified in all samples with very small variability. Although both types of nanoparticles have similar amounts of bonded proteins, very slight differences in the composition of the corona might explain the variation observed in the uptake and biotransformation of these nanoparticles in Caco-2 and RAW 264.7 cells. Cytotoxicity was also studied using a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Controlling nanoparticles’ reactivity to the biological environment by deciding on its surface functionalization may suggest new routes in the control of the biodistribution, biodegradation and clearance of multifunctional nanomedicines

Beyond Traditional Hyperthermia. In vivo Cancer Treatment with Magnetic-Responsive Mesoporous Silica Nanocarriers

In this study we present an innovation in the tumor treatment in vivo mediated by magnetic mesoporous silica nanoparticles (MMSNs). This device was built with iron oxide magnetic nanoparticles embedded in a mesoporous silica matrix and coated with an engineered thermoresponsive polymer. The magnetic nanoparticles act as internal heating sources under an alternating magnetic field (AMF) that increase the temperature of the surroundings, provoking the polymer transition and consequently the release of a drug trapped inside the silica pores. By a synergic effect between the intracellular hyperthermia and chemotherapy triggered by AMF application, significant tumor growth inhibition was achieved in 48 hours after treatment. Furthermore, the small magnetic loading used in the experiments indicates that the treatment is carried out without a global temperature rise of the tissue, which avoids the problem of the necessity to employ large amounts of magnetic cores, as is common in current magnetic hyperthermia

Dependence of intracellular magnetic nanoparticles amount in the apoptotic death pathway triggered by magnetic hyperthermia treatment

Trabajo presentado a la 4th Spanish Conference on Biomedical Applications of Nanomaterials, celebrada online del 2 al 4 de junio de 2021.Peer reviewe

Jon Etxaide

Donostiako idazlea. Itzultzaile, artikulugile eta batez ere, literatura-sortzaile: antzerkia, eleberria, ipuinak

Antonio María Labayen

Idazle oparoa. Euskal antzerkiaren pizkundearen eragileetako bat. Antzerkigintzan nabarmendu bazen ere, genero eta gai asko jorratu zituen: itzulpen-lanak, biografiak, antzerki-mota desberdinak, bertsoak, artikuluak, entseguak, kritika-lanak eta euskara batuaren inguruko liburuak. Garaiko aldizkarietan topa daitezke haren lan ugari. Antzerti aldizkaria sortu eta zuzendu zuen. Komediak zein dramak idatzi (Jokua ez da errenta, Malentxo alargun, Galtzaundi, Su eta gar) eta itzuli (Gizona eta kidea, Su-emailleak, Neskatilla ezkongai) landu zituen. Biografiak (Elizanburu, Muñagorri) eta saiakerak (Tajuz eta Zentzuz) ere idatzi zituen. Euskaltzain osoa izan zen

Bernardo Estornes Lasa

Historialaria eta editorea. Euskaldun berria. Erbestean bizi izan zen. Lan ugari idatzi zituen garaiko aldizkarietan. Euskararen jatorria eta historia (Geografía histórica de la lengua vasca, Antología literaria vasca, Sobre historia y orígenes de la Lengua Vasca, Erronkariko uskararen hiztegia) eta Euskal Herriko historia (Historia del País Vasco, Eneko Arista, El Ducado de Vasconia, Orígenes de los Vascos) izan ditu idazgai nagusi. Euskaraz ere idatzi zituen zenbait lan: Erronkari, Sabin euskalduna. Auñamendi argitaletxea sortu zuen. Enciclopedia General Ilustrada del País Vasco sortu eta bultzatu zuen. Euskaltzain urgazlea eta ohorezkoa