Biomimetic Magnetic Nanocarriers Drive Choline Kinase Alpha Inhibitor inside Cancer Cells for Combined Chemo-Hyperthermia Therapy

Choline kinase a1 (ChoKa1) has become an excellent antitumor target. Among all the inhibitors synthetized, the new compound Ff35 shows an excellent capacity to inhibit ChoKa1 activity. However, soluble Ff35 is also capable of inhibiting choline uptake, making the inhibitor not selective for ChoKa1. In this study, we designed a new protocol with the aim of disentangling whether the Ff35 biological action is due to the inhibition of the enzyme and/or to the choline uptake. Moreover, we offer an alternative to avoid the inhibition of choline uptake caused by Ff35, since the coupling of Ff35 to novel biomimetic magnetic nanoparticles (BMNPs) allows it to enter the cell through endocytosis without interacting with the choline transporter. This opens the possibility of a clinical use of Ff35. Our results indicate that Ff35-BMNPs nanoassemblies increase the selectivity of Ff35 and have an antiproliferative effect. Also, we demonstrate the effectiveness of the tandem Ff35-BMNPs and hyperthermia.This research was funded by the Ministerio de Economía y Competitividad (CGL2013-46612 and CGL2016-76723 projects), Ramón y Cajal programme (RYC-2014-16901) and the Fondo Europeo de Desarrollo Regional (FEDER). Also, this research was aided by the Andalusian regional government (CTS-236)

Caracterización de nanosistemas magnéticos y su aplicación en quimioterapia dirigida y nanorremediación

Esta Tesis Doctoral ha sido realidad en el Departamento de Microbiología (Facultad de Ciencias) de la Universidad de Granada durante los años 2015-2019 dentro del grupo de investigación Mixobacterias. Para realizar esta Tesis Doctoral la doctoranda ha disfrutado de: Una ayuda para la Formación de Personal Investigador (F.P.I.) (BES-2014- 071206) a cargo del proyecto CGL2013-46612-P del Ministerio de Economía y Competitividad, cuya investigadora principal es la Dra. Concepción Jiménez López, Profesora Titular del Departamento de Microbiología de la Universidad de Granada. Cuatro ayudas para la realización de Estancias Breves (E.E.B.B.) en centros extranjeros, con referencias: EEBB-I-16-11093 (92 días), EEBB-I-17-12558 (92 días), EEBB-I-18-12984 (102 días), EST2019-013134-I (60 días), también financiadas por el Ministerio de Economía y Competitividad.Las nanopartículas de magnetita (Fe3O4) han despertado un gran interés en el campo de la biotecnología debido a su alta relación superficie/volumen, que puede utilizarse para anclar cantidades relativamente altas de moléculas específicas, y porque pueden manipularse fácilmente utilizando un campo magnético externo, debido a su alto momento magnético en comparación con otros óxidos de hierro. Se pueden sintetizar de manera inorgánica utilizando diferentes procesos pero, generalmente, a altas temperaturas y presiones, lo que implica altos costes de producción. Además, estas magnetitas producidas químicamente no suelen presentar todas las características deseables (alta magnetización, tamaños y morfologías adecuadas, biocompatibilidad o alta estabilidad química) para ciertas aplicaciones biomédicas. Las bacterias magnetotácticas (MTB) sintetizan magnetosomas, compuestos de Fe3O4 monocristalino envuelto por una membrana, mediante un estricto control genético en el que intervienen proteínas únicas llamadas proteínas asociadas a magnetosomas (MAPs). Este proceso de biomineralización controlada (BCM) da como resultado nanopartículas de magnetita con estructuras cristalinas perfectas, alta pureza química, morfologías alargadas y una estrecha distribución de tamaños entre 30 y 120 nm, que hace que estos cristales sean de dominio magnético único y, en consecuencia, la nanopartícula magnética ideal. Sin embargo, no es posible escalar a nivel industrial el cultivo de MTB debido a sus exigentes condiciones nutricionales y su lento crecimiento, por lo que los magnetosomas no pueden obtenerse en grandes cantidades. De hecho, este es el cuello de botella para la aplicación de los magnetosomas en nanotecnología. En este contexto, una de las alternativas propuestas es la biomimética, es decir, la producción in vitro de nanopartículas magnéticas similares a los magnetosomas mediante la utilización de MAPs, dado que la interacción preferencial de MAPs con el cristal de magnetita se ha sugerido para explicar las propiedades únicas de las magnetitas producidas por las MTB. Sin embargo, todavía hay muchas incógnitas relacionadas con las estructuras y funciones de la mayoría de las MAPs. Por lo tanto, desde un punto de vista biológico, así como para la aplicación práctica de estas nanopartículas de magnetita biomiméticas (BMNPs), comprender este proceso de BCM, el único conocido hasta ahora en el dominio Bacteria, representa un desafío de extraordinaria importancia.Magnetite (Fe3O4) nanoparticles are of great interest in biotechnology field since they have a large area surface, which can be used for anchoring relatively large amounts of specific molecules, and can be easily manipulated by using an external magnetic field because of their high magnetic moment per particle compared to other iron oxides. They can be synthesized inorganically using different processes but, generally, performed at high temperatures and pressures, which involves high costs of production. Moreover, these chemically-produced magnetites usually do not have all desirable features (i.e. high magnetization, consistent sizes and morphologies, biocompatibility or high chemical stability) for certain biomedical applications. Magnetotactic bacteria (MTB) synthesize magnetosomes comprised of membrane-enveloped single crystalline Fe3O4 by a strict genetic control in which are involved unique proteins called magnetosomeassociated proteins (MAPs). This controlled biomineralization process (BCM) results in nanomagnetites with perfect crystal structures, high chemical purity, elongated morphologies and narrow size distribution (between 30 and 120 nm), making these crystals a single magnetic domain and, in consequence, the ideal magnetic nanoparticles. However, the scale up of such a production is not possible at present because of the exigent nutrition conditions of MTB and their slow growth, so magnetosomes cannot be obtained in large quantities. In fact, this is the bottleneck for the application of magnetosomes in nanotechnology. In this context, one of the proposed alternatives is biomimetic, i.e the in vitro production of magnetosome-like magnetic nanoparticle mediated by MAPs, since preferential interaction of MAPs with magnetite crystal has been suggested to explain the unique properties of the magnetites produced by MTB. However, there are still many unknowns related to the structure and function of most of the MAPs. So from a biological standpoint, as well as for the potential application of this biomimetic magnetite nanoparticles (BMNPs), understanding this BCM, the only one known so far in the domain Bacteria, represents a challenge of extraordinary importance.Tesis Univ. Granada.CGL2013-46612-P del Ministerio de Economía y CompetitividadEEBB-I-16-11093 (92 días), EEBB-I-17-12558 (92 días), EEBB-I-18-12984 (102 días), EST2019-013134-I (60 días) Ministerio de Economía y Competitivida

Museo del aire en Cuatro Vientos [Hojas Resumen]

Museo del aire en Cuatro Viento

Biomimetic Magnetite Nanoparticles as Targeted Drug Nanocarriers and Mediators of Hyperthermia in an Experimental Cancer Model

Simple Summary: The application of simultaneous and di erent strategies to treat cancer appears a promising therapeutic approach. Herein we proposed the application of chemotherapy combined with a magnetic nanocarrier delivery system to an in vitro and an in vivo experimental mammary carcinoma model. Drug-loaded biomimetic magnetic nanoparticle can be directed and concentrated on the tumor cells or site by the apposition of a magnet. Moreover, these nanoparticles can respond to an alternating magnetic field by developing hyperthermia around 43 C, a temperature at which tumor cells, but not healthy cells, are particularly sensitive and thus induced to death. Indeed, when this nanoformulation is injected in vivo in the tumor site, and hyperthermia is generated, the combined chemo-thermal therapy mediated by these drug-loaded magnetic nanoparticles have a stronger therapeutic benefit compared to that carried out by the chemotherapeutic alone. These nanoformulation and strategy are thus promising tools for translational applications in cancer therapy. Abstract: Biomimetic magnetic nanoparticles mediated by magnetosome proteins (BMNPs) are potential innovative tools for cancer therapy since, besides being multifunctional platforms, they can be manipulated by an external gradient magnetic field (GMF) and/or an alternating magnetic field (AMF), mediating targeting and hyperthermia, respectively. We evaluated the cytocompatibility/cytotoxicity of BMNPs and Doxorubicin (DOXO)-BMNPs in the presence/absence of GMF in 4T1 and MCF-7 cells as well as their cellular uptake. We analyzed the biocompatibility and in vivo distribution of BMNPs as well as the e ect of DOXO-BMNPs in BALB/c mice bearing 4T1 induced mammary carcinomas after applying GMF and AMF. Results: GMF enhanced the cell uptake of both BMNPs and DOXO-BMNPs and the cytotoxicity of DOXO-BMNPs. BMNPs were biocompatible when injected intravenously in BALB/c mice. The application of GMF on 4T1 tumors after each of the repeated (6 ) iv administrations of DOXO-BMNPs enhanced tumor growth inhibition when compared to any other treatment, including that with soluble DOXO. Moreover, injection of DOXO-BMNPs in the tumor combined with application of an AMF resulted in a significant tumor weight reduction. These promising results show the suitability of BMNPs as magnetic nanocarriers for local targeted chemotherapy and as local agents for hyperthermia.Spanish Government RYC-2014-16901Junta de Andalucía, Programa Operativo FEDER 2014-2020 A1-FQM-341-UGR18 C-FQM-497-UGR18Progetto di Ricerca Fondi di Ateneo per la Ricerca-FAR 2017 "Development of innovative biological materials for the functional regeneration of cardiac tissue models"Ministerio de Economia y Competitividad from Spain CGL2016-76723European Union (EU)Junta de Andalucía A-BIO-376-UGR18Unidad Científica de Excelencia of the University of Granada UCE-PP2016-05Ministry of Economy and Competitiveness, Spain EST2019-013134-I EEBB-I-17-12558 5

The role of sleep and wakefulness in incidental language learning: one performance, two representations

info:eu-repo/semantics/nonPublishe

The role of sleep and wakefulness in incidental statistical language learning: one performance, two representations

p. 12info:eu-repo/semantics/nonPublishe

Nanopartículas magnéticas biomiméticas que comprenden MamC

Número de publicación: 2 758 400. Número de solicitud: 201831064La presente invención proporciona nanopartículas biomiméticas superparamagéticas que comprenden magnetita, las cuales se pueden fabricar mediante un proceso escalable. Además, estas nanopartículas presentan unas prometedoras propiedades, ya que, si se funcionalizan, pueden convertirse en transportadores de fármacos o agentes de contraste para la obtención de imágenes clínicas. Se pueden usar en entornos clínicos también para purgar médula ósea, así como separadores de moléculas y/o en aplicaciones medioambientales como biosensores. Estas nanopartículas, acopladas con un fármaco, se pueden encapsular en liposomas, obteniendo magnetoliposomas, los cuales pueden funcionalizarse para su uso en la administración/liberación dirigida de fármacos. Además, las mezclas de magnetoliposomas (tanto funcionalizados como sin funcionalizar con un agente de direccionamiento) y nanopartículas magnéticas biomiméticas funcionalizadas o liposomas que contengan mezclas de BMNPs funcionalizadas y MNPs pueden usarse parar combinar diferentes tratamientos como, por ejemplo, la administración/liberación dirigida de fármacos y la hipertermia.Universidad de Granad

Functionalized Biomimetic Magnetic Nanoparticles as Effective Nanocarriers for Targeted Chemotherapy

Novel MamC-mediated biomimetic magnetic nanoparticles (BMNPs) are proposed as valuable carriers for targeted chemotherapy because of the size (36 \ub1 12 nm) and of surface properties conferred by MamC coating. They are super-paramagnetic at room and body temperatures, have a large magnetic moment per particle, mediate hyperthermia, are cytocompatible, and, having a negative surface charge at physiological pH, can be efficiently coupled with DOXOrubicin (DOXO) and a monoclonal antibody (mAb) directed against the human Met/hepatocyte growth factor receptor (overexpressed in many cancers) displaying coupling stability, while releasing DOXO at acidic pH. This release can be enhanced by hyperthermia. The DOXO-mAb-BMNPs selectively recognize Met, bind efficiently to Met+ tumor cells, and discharge DOXO within their nuclei more efficiently than DOXO-BMNPs, exerting cytotoxicity. These data represent proof of concept for future in vivo experi-ments in which the controlled dual targeting (mAb-mediated and magnetic) approach and combined (chemotherapy and hyperthermia) therapy will be studie