Publication: Nanotransportadores basados en sílice mesoporosa para tratamiento antitumoral
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2017-07-13
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Universidad Complutense de Madrid
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Abstract
Esta tesis doctoral se centra en el diseño, síntesis y caracterización de nanosistemas para el tratamiento del cáncer basados en la utilización de nanopartículas mesoporosas de sílice (MSNs). La quimioterapia tradicional carece de selectividad hacia las masas tumorales, por lo que los fármacos anticancerígenos causan graves efectos secundarios en los pacientes. Además, la alta toxicidad de estos fármacos limita la dosis y merma la eficacia de los tratamientos. La aplicación de nanomateriales en oncología puede mejorar la acción de los agentes de quimioterapia tradicionales en términos de biodisponibilidad, especificidad y seguridad, gracias a su tamaño nanométrico. El objetivo de la presente tesis doctoral ha sido desarrollar nuevos dispositivos para la administración controlada de fármacos (ACF) que mitiguen los efectos adversos de las terapias sistémicas con citotóxicos. Para ello es necesario liberar la carga antitumoral de manera muy localizada. Esto se consigue mediante la acumulación de los nanotransportadores en la zona tumoral. De esta manera se alcanzan altas concentraciones de fármaco solo en el tejido diana, lo que resulta en una menor toxicidad para el paciente y por tanto una disminución en los efectos secundarios de la terapia. Las MSNs muestran excelentes propiedades para transportar fármacos antitumorales debido a su alta área superficial y volumen de poro, actuando así como reservorio de citotóxicos hasta la acumulación de las MSNs en el tejido diana. En esta tesis doctoral, se han estudiado diferentes aproximaciones para la ACF como son: la liberación asistida por campos magnéticos alternos, la generación de agentes citotóxicos in situ y la obtención de nanocápsulas de polidopamina; esta última utilizando nanopartículas mesoporosas de sílice como plantilla. Para la obtención de dispositivos de liberación de fármacos sensibles a campos magnéticos alternos (CMA), se encapsularon nanopartículas de γ‐Fe2O3/Fe3O4 en matrices mesoporosas de sílice obteniendo nanopartículas magnéticas de sílice mesoporosa (MMSNs). Para retener fármacos en el interior de la matriz de sílice, las MMSNs se recubrieron con diferentes co‐polímeros termosensibles formados mediante combinaciones de los monómeros N‐isopropilacrilamida, N‐hidroximetilacrilamida, N,N‐metilenbisacrilamida y polietilenimina (NIPAM,NHMA,MBA,PEI). Estos polímeros sintetizados experimentan una transición linealglobular a temperaturas entre los 37 ºC y los 42 ºC. El cambio conformacional de la capa polimérica puede controlar el proceso de liberación de las especies alojadas en el interior de la sílice, permitiendo o impidiendo su liberación. El campo magnético alterno fue escogido como estímulo para liberar la carga citotóxica ya que es altamente penetrante en los tejidos, no es invasivo y es capaz de inducir un calentamiento en ciertas nanopartículas magnéticas. Este calentamiento induce un cambio conformacional en la capa polimérica instalada en la superficie, liberando la carga citotóxica alojada en el interior de los nanotransportadores...
This dissertation focuses on the design, synthesis and characterization of nanosystems for the cancer treatment based on the use of mesoporous silica nanoparticles (MSNs). Traditional chemotherapy has no selectivity toward tumor masses, therefore the administered anticancer drugs cause serious side effects in patients. In addition, the high toxicity of these drugs restricts the dosage and diminishes the effectiveness of the treatments. Application of nanomaterials in oncology can enhance the action of traditional chemotherapy agents in terms of bioavailability, specificity and security, thanks to their nanometer size. The aim of this thesis was to develop new drug delivery systems (DDS) that mitigate the adverse effects of systemic cytotoxic therapies. In order to accomplish this goal, it is necessary to release the antitumoral payload in a controlled manner. This is achieved through the accumulation of the nanocarriers in the tumor area. In this way, high concentrations of drugs are released only in the target tissue, which results in a lower toxicity to the patient and therefore a decrease in side effects of the therapy. The MSNs show excellent properties for transporting antitumor drugs due to their high surface area and pore volume, thus acting as a reservoir of cytotoxic compounds until the accumulation of the MSNs in the target tissue. In this thesis, different approaches to DDS have been studied: drug release assisted by alternating magnetic fields, the in‐situ generation of cytotoxic agents and polidopamine nanocapsules formation; the latter using mesoporous silica nanoparticles as a template. The magnetic sensitive DDS were obtained by the encapsulation of γ‐Fe2O3 / Fe3O4 nanoparticles in mesoporous silica matrices, termed as magnetic mesoporous silica nanoparticles (MMSNs). To retain drugs inside the silica matrix, the MMSNs were coated with different thermosensitive copolymers, formed by combinations of monomers N‐isopropylacrilamide and N‐hydroximethylacrilamide, N,N‐methylenebisacrylamide and polyethylenimine (NIPAM/NHMA/MBA/PEI). These polymers undergo a lineal‐to‐globular transition between 37 ° C and 42 ° C. The conformational change of the polymer layer can control the release process of the housed species in the interior of the silica matrix, allowing or preventing its release. The alternating magnetic field was chosen as stimulus to release the cytotoxic payload since it is highly penetrating in tissues, not invasive and capable of inducing local warming by certain magnetic nanoparticles. The temperature increase induces a conformational change in the polymer coating, allowing the releasing of cytotoxic compounds hosted inside the nanocarriers...
This dissertation focuses on the design, synthesis and characterization of nanosystems for the cancer treatment based on the use of mesoporous silica nanoparticles (MSNs). Traditional chemotherapy has no selectivity toward tumor masses, therefore the administered anticancer drugs cause serious side effects in patients. In addition, the high toxicity of these drugs restricts the dosage and diminishes the effectiveness of the treatments. Application of nanomaterials in oncology can enhance the action of traditional chemotherapy agents in terms of bioavailability, specificity and security, thanks to their nanometer size. The aim of this thesis was to develop new drug delivery systems (DDS) that mitigate the adverse effects of systemic cytotoxic therapies. In order to accomplish this goal, it is necessary to release the antitumoral payload in a controlled manner. This is achieved through the accumulation of the nanocarriers in the tumor area. In this way, high concentrations of drugs are released only in the target tissue, which results in a lower toxicity to the patient and therefore a decrease in side effects of the therapy. The MSNs show excellent properties for transporting antitumor drugs due to their high surface area and pore volume, thus acting as a reservoir of cytotoxic compounds until the accumulation of the MSNs in the target tissue. In this thesis, different approaches to DDS have been studied: drug release assisted by alternating magnetic fields, the in‐situ generation of cytotoxic agents and polidopamine nanocapsules formation; the latter using mesoporous silica nanoparticles as a template. The magnetic sensitive DDS were obtained by the encapsulation of γ‐Fe2O3 / Fe3O4 nanoparticles in mesoporous silica matrices, termed as magnetic mesoporous silica nanoparticles (MMSNs). To retain drugs inside the silica matrix, the MMSNs were coated with different thermosensitive copolymers, formed by combinations of monomers N‐isopropylacrilamide and N‐hydroximethylacrilamide, N,N‐methylenebisacrylamide and polyethylenimine (NIPAM/NHMA/MBA/PEI). These polymers undergo a lineal‐to‐globular transition between 37 ° C and 42 ° C. The conformational change of the polymer layer can control the release process of the housed species in the interior of the silica matrix, allowing or preventing its release. The alternating magnetic field was chosen as stimulus to release the cytotoxic payload since it is highly penetrating in tissues, not invasive and capable of inducing local warming by certain magnetic nanoparticles. The temperature increase induces a conformational change in the polymer coating, allowing the releasing of cytotoxic compounds hosted inside the nanocarriers...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Química Orgánica e Inorgánica, leída el 13/10/2016