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Title: Novel ᴫ-Functional Components of Micro- and Nanoparticles for Nanomedicine
Author: Alea Reyes, María Elisa
Director/Tutor: Pérez García, M. Lluïsa (Maria Lluïsa)
González Gazulla, Asensio
Keywords: Nanomedicina
Issue Date: 17-Jul-2017
Publisher: Universitat de Barcelona
Abstract: [eng] The present thesis is included in the area of Nanomedicine and supramolecular chemistry, focused on the design and preparation of different nano and microtools for delivery, therapy and sensing. Initially, the synthesis and characterization of structures derived from gemini-type pyridinium amphiphiles were reported. They have the ability to play multiple roles such as transfer agent and stabilizer, as well as ionophores, and also are responsible for the preparation, stability, and delivery properties of the gold nanoparticles (AuNPs), which gold core is stabilized by the anions present in the bis-pyridinium salts. The gold nanoparticles synthesized proved stable and to have low polydispersity and showed the ability to incorporate piroxicam. Therefore, the in vitro release of 3·AuNPs and 4·AuNPs at two different pH values (7.4 and 5.5) proves a faster release profile at pH 7.4, indicating their suitability as promising materials for delivery in physiological conditions. On the other hand, this report also includes the synthesis and characterization of porphyrin derivatives as photosensitizers in particular metalloporphyrins and their subsequent incorporation to different vehicles such as gold nanoparticles, microparticles (polysilicon-gold) and gold nanorods for their use in photodynamic therapy, due to their capacity to produce reactive oxygen species after irradiation, inducing the cell death. The successfully functionalization of this vehicles were followed by UV-visible absorption spectroscopy, High-Resolution Transmission Electron Microscopy (HRTEM) or Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), X-ray Photoelectron Spectroscopy (XPS), Thermogravimetric analysis (TGA), Fluorescence Spectroscopy, contact angle measurements and fluorescence microscopy. Additionally, the formation of self-assembled monolayers (SAMs) on polysilicon substrates (wafers and microparticles) was investigated, using different immobilization methodologies (covalent and non-covalent) in order to obtain a functionalization protocol which can be easily repetitive and effective. Firstly, this substrates were functionalized with two groups of compounds (pyridinium and imidazolium salts) used as host in the subsequent incorporation of the Zn(II) porphyrin with a high potential to be used in PDT. The immobilization of the different hosts was following by contact angle, while the presence of the Zn(II) porphyrin was confirmed by fluorescence microscopy. The concentration of the photosensitizer incorporated on the polysilicon microparticles was found in the range of 2.2-2.6 µM. On the other hand, a release study of the incorporated porphyrin during a week was performed, resulting in a very low percentage of the total incorporated porphyrin. This result indicates that a stable interaction is established between the porphyrin and the host on the surface. Finally, we describe the non-covalent functionalization of polysilicon substrates (wafers and microparticles) with gemini-type amphiphilic bipyridinium salts (1·4PF6- 3·4PF6), witch act as host for the subsequent incorporation of the neurotransmitters Dopamine hydrochloride (Dop), Serotonin hydrochloride (Ser), Adrenaline hydrochloride (Adr) and Noradrenaline hydrochloride (Nor), in order to obtain the optimum system potentially suitable for sensors of compounds with electron rich groups. The successfully functionalization of the polysilicon substrates was followed by contact angle measurements. Additionally, fluorescence microscopy was used to detect the complex bis-bipyridinium salt-neurotransmitter in both substrates showed an increase on the fluorescence intensity on the substrates functionalized with the bis- bipyridinium salts and subsequent incorporation of the neurotransmitters respect to the controls. Polysilicon surfaces functionalized with 1·4PF6 and subsequent incorporation of Dop or Ser showed the higher values of fluorescence intensity of 71 and 72%, respectively. In this context the bis-bipyridinium 1·4PF6 and neurotransmitters Dop or Ser were selected to functionalize polysilicon microparticles. 1·4PF6 was neither cytotoxic nor genotoxic to the cell lines studied 3T3/NIH, HepG2 and CaCo-2 at the maximum concentration tested of 500 µg/mL. With our work, we set up the non- covalent functionalization methodology to develop a microsystem potentially useful for drug sensors purposes.
[spa] La presente tesis se incluye en el área de Nanomedicina y química supramolecular, enfocada en el diseño y preparación de diferentes sistemas nano y micro estructurados para la liberación, terapia y detección. Inicialmente, fueron sintetizadas y caracterizadas un grupo de moléculas anfifílicas basadas en sales de piridinio tipo gemini, las cuales se caracterizan por desempeñar múltiples funciones, tales como: agente de transferencia y estabilizador, así como ionóforos, además de ser responsables de la preparación y estabilidad de nanopartículas de oro. Las nanopartículas de oro sintetizadas resultaron ser estables y de baja polidispersión, además de ser capaces de incorporar fármacos como piroxicam y liberarlo a pH 7,4 y 5,5, obteniéndose un perfil de liberación más rápido a pH 7,4. Por otro lado, la tesis también describe la preparación de nano y microsistemas para su aplicación en terapia fotodinámica (PDT). La PDT se basa en el uso de moléculas específicas llamadas fotosensibilizadores, que al ser irradiadas, activan el proceso de la muerte celular debido a la formación de radicales libres de oxígeno. La combinación de la utilización de nano y micro vehículos modificadas con un fotosensibilizador resulta un buen objetivo que podría mejorar la terapia antitumoral, disminuyendo los efectos secundarios de la misma. Concretamente, se describe la preparación de nuevos fotosensibilizadores derivados de las porfirinas en particular metaloporfirinas con el fin de ser incorporados en diferentes vehículos como nanopartículas de oro, micropartículas (polisilicio y polisilicio-oro) además de nanohilos de Cobalto-Niquel recubiertos con oro. También se detalla el estudio de la capacidad de los nuevos nano and microsistemas obtenidos, de producir oxígeno singlete como elemento inductor de la apoptosis celular. Estos estudios, demuestran la posibilidad de dichos nanos y microsistemas para ser usados en PDT. Finalmente, micropartículas de polisilicio fueron no covalentemente funcionalizadas con sales de bipiridinio tipo gemini como moléculas ᴫ-aceptoras que actúan como huésped en la subsecuente incorporación de neurotransmisores como moléculas ᴫ-donoras. De esta forma fue posible establecer la metodología de funcionalización no covalente para desarrollar un microsistema potencialmente útil para propósitos de sensores de moléculas con grupos ricos en electrones como es el caso de los neurotransmisores estudiados.
Appears in Collections:Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèutica

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