Mojica Pisciotti, Mary L. (2015) Desarrollo de nanopartículas magnéticas para su utilización en el tratamiento médico: Hipertermia. / Development of magnetic nanoparticles for the hyperthermia medical treatment. Tesis Doctoral en Física, Universidad Nacional de Cuyo, Instituto Balseiro.
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Resumen en español
En nanomedicina, la hipertermia es una de los procedimientos más prometedores en el área de tratamiento del cáncer, consiste en promover la muerte celular como consecuencia del incremento de la temperatura local en un tejido tumoral. Este calentamiento puede ser mediado por el uso de nanopartículas magnéticas (MNPs) que son previamente absorbidas por la células cancerígenas. De esta manera al interactuar con un campo magnético alterno (AMF) las MNPs reciben energía magnética del campo y la transforman en energía térmica alcanzando un aumento mensurable de la temperatura local. Este calentamiento agresivo puede causar muerte celular principalmente a través de estrés o daño en las membranas de las organelas celulares. Luego, considerando que por muchos años los tratamientos médicos contra el cáncer han consistido básicamente en cirugía, radioterapia y quimioterapia solos o en cualquier combinación posible, la hipertermia parece ser un método esperanzador para ayudar en el tratamiento de esta enfermedad. Las terapias comunes son invasivas y pueden producir efectos adversos no deseados en el organismo, contrariamente a lo esperado con hipertermia. Por lo tanto, es de gran interés diseñar y producir MNPs que puedan ser confiables para la terapia propuesta. En este trabajo, estudiamos nanopartículas superparamagnéticas de óxidos de hierro (SPIONs) debido a su biocompatibilidad y propiedades magnéticas relevantes que son fundamentales para la efectividad de la técnica. SPIONs de Fe_3O_4 fueron sintetizadas a través del método de descomposición térmica a alta temperatura de acetilacetonato de hierro (Fe(acac)3) que ofrece un control óptimo sobre el tamaño y la dispersión. Obtuvimos SPIONs cristalinas de distintos tamaños de acuerdo con microscopía de transmisión de electrones y una caracterización exhaustiva de sus propiedades morfológicas y magnéticas se llevó a cabo. Distintas técnicas experimentales fueron usadas con este propósito. Una vez que las SPIONs fueron sintetizadas pueden ser suspendidas en solventes orgánicos. Las SPIONs exhibieron alta magnetización de saturación y comportamiento supeparamagnético a temperatura ambiente. Luego, a través de algunos procesos químicos de intercambio de ligandos y encapsulación con diferentes moléculas orgánicas tales como DEXTRAN, derivativos de polietilenglicol y fosfolípidos, modificamos el recubrimiento de las nanopartículas para suspenderlas en medio acuoso, una característica deseable para algunas aplicaciones, especialmente hipertermia. Usando ambos conjuntos de SPIONs, hicimos mediciones de la absorción específica de potencia (SPA) en un dispositivo comercial con un AMF de 200 Oe (15.9 kA/m) con frecuencias entre 200 y 900 kHz. Las mediciones mostraron altos valores de SPA, del orden de cientos de W/g. La dependencia del SPA con la viscosidad del medio así como también con los aspectos morfológicos de las nanopartículas fue también estudiada. Estos resultados fueron explicados a través de una teoría simple y bien conocida. Reformulamos conceptualmente la misma para explicar con un diagrama el comportamiento del SPA a través de la identificación de los mecanismos de calentamiento para una muestra de nanopartículas de acuerdo con sus propiedades. Este diagrama permitió además estimar los valores de SPA usando la teoría correcta en cada caso. Finalmente, algunos experimentos biológicos in vitro e in vivo fueron diseñados para estudiar el efecto de las SPIONs en distintas líneas celulares. La viabilidad celular relacionada con la toxicidad de las nanopartículas con diferentes recubrimientos fue profundamente analizada. Usando algunas técnicas experimentales de última tecnología tales como microscopía Dual-Beam FIB/SEM se pudo observar y presentar en este trabajo imágenes sobre la capacidad celular para incorporar SPIONs. También, la biodistribución de SPIONs en un sistema in vivo (ratones Balb/c) fue examinada y se presentan varias conclusiones acerca de la influencia de los parámetros de las nanopartículas en su localización dentro del organismo.
Resumen en inglés
In nanomedicine, the hyperthermia is one of the most promising procedures in the field of cancer treatment, it consists in promoting cell death by increasing the local temperature in a tumoral tissue. This heating can be mediated by using magnetic nanoparticles (MNPs) that are previously absorbed by cancer cells. Thus they interact with an alternating magnetic field (AMF) in such way that they receive energy from the field and then transform it into thermal energy achieving a measurable rise in the local temperature. This aggressive heating could cause cellular death mainly through stress or damage in the cell organelles’ membranes. Thus, considering that for some years the medical cancer treatments have consisted basically of surgery, radiotherapy and chemotherapy alone or in any possible combination, the hyperthermia seems to be a hopeful way to help dealing with this illness. The common therapies are invasive and can produce some undesirable adverse effects in the organism, contrary to what is expected from hyperthermia. Then, it is of great interest to design and produce MNPs that can be reliable for the proposed therapy. In this work, we studied superparamagnetic iron oxide nanoparticles (SPIONs) due to its biocompatibility and relevant magnetic properties that are fundamental for the effectiveness of the technique. Fe_3O_4 SPIONs were synthesized through the method of high temperature decomposition of iron acetylacetonate (Fe(acac)3) which offers an optimal control over size and dispersion. We obtained well-crystalline SPIONs of different sizes according to electron transmission microscopy and an exhaustive characterization of their morphological and magnetic properties was performed. Different experimental techniques were used for this purpose. Once the SPIONs were synthesized they could be suspended in organic solvents. The SPIONs exhibited high saturation magnetization and superparamagnetic behavior at room temperature. Then, through some chemical procedures of ligand exchange and encapsulation with different organic molecules such as DEXTRAN, polyethlylene glycol derivatives and phospholipids, we modified the nanoparticles’ covering in order to suspend them in aqueous media, a desirable feature for some applications, specially hyperthermia. Using both sets of SPIONs, we performed specific power absorption (SPA)measurements on a commercial device with an AMF of 200 Oe (15.9 kA/m) with frequencies between 200 and 900 kHz. The measurements showed high SPA values, the order of hundreds of W/g. The SPA dependence on the viscosity of the media as well as on the morphological aspects of the nanoparticles was also studied. These results were explained through a simple and well-known theory. We conceptually reformulate it in order to explain the SPA behaviour through the identification in a diagram of the heating mechanisms for a nanoparticles sample according to its properties. This diagram allowed us to estimate the SPA values using the proper theory in each studied case. Finally, some in vitro and in vivo biological experiments were designed for studying the effect of SPIONs in different cell lineages. The cell viability related to the nanoparticles toxicity with different coverings was deeply analyzed. Using some up-to-date experimental techniques, such as Dual-Beam FIB/SEM microscopy, the cells capacity to uptake SPIONs was observed and presented in this work. Also, the biodistribution of SPIONs in an in vivo system (Balb/c mice) was examined and fair conclusions about the influence of the nanoparticles’ parameters in their location inside the organism were reached.
| Tipo de objeto: | Tesis (Tesis Doctoral en Física) |
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| Palabras Clave: | Nanoparticles; Nanopartículas; Hyperthermia; Hipertermia; Neoplasms; Neoplasmas; Magnetism; Magnetismo; Superparamagnetism; Superparamagnetismo; Therapy; Terapia [Nanomedicine; Nanomedicina; MNPs; Magnetic nanoparticles; Nanoparticulas magnéticas] |
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| Materias: | Física Medicina > Oncología Medicina |
| Divisiones: | Investigación y aplicaciones no nucleares > Física > Resonancias magnéticas |
| Código ID: | 525 |
| Depositado Por: | USUARIO INVÁLIDO |
| Depositado En: | 23 Mar 2016 11:30 |
| Última Modificación: | 23 Mar 2016 11:30 |
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