Hipertermia magnética basada en nanopartículas de óxido de hierro como terapia antitumoral: del cultivo celular tridimensional al modelo in vivo
- Autores: Lilianne de la Caridad Beola Guibert
- Directores de la Tesis: Lucia Gutierrez Marruedo (dir. tes.), María Valeria Grazú Bonavía (dir. tes.), Laura Asín Pardo (dir. tes.)
- Lectura: En la Universidad de Zaragoza ( España ) en 2020
- Idioma: español
- Programa de doctorado: Programa de Doctorado en Ciencia Analítica en Química por la Universidad de Zaragoza
- Materias:
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- Resumen
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.
