Alleva, Maria
Martínez de la Fuente, Jesús (dir.) ; Moros Caballero, María (dir.)
Universidad de Zaragoza,
2024
Resumen: Esta tesis explora el potencial de la nanotecnología para mejorar la eficacia de los sistemas de administración de fármacos (DDS) y dirigirlos al cerebro. En este trabajo nos centramos en los retos que plantean las barreras biológicas para el paso a su través de agentes terapéuticos, en particular la barrera de la mucosa nasal, lo que puede disminuir su eficacia. Hemos estudiado la administración de fármacos al cerebro desde la nariz, mediante una exploración exhaustiva del destino de las nanocápsulas (NC) de base polimérica, monitorizándolas mediante el fenómeno de transferencia de energía por resonancia de Förster (FRET). La optimización de las estrategias de síntesis y sustitución ha dado lugar a NCs- FRET estables, con aplicaciones potenciales en la administración de fármacos y su seguimiento en células. En el Capítulo 1 también se ha establecido un modelo celular que imita el epitelio de la mucosa nasal utilizando células Calu-3, lo que ha permitido investigar el destino y las interacciones de las NC con estas células. Para demostrar si estas NCs podían atravesar la barrera de manera intacta y por tanto tenían potencial para la administración de fármacos se ha puesto a punto otro modelo celular utilizando células Balb/c como células diana, colocadas en el lado opuesto de la barrera. En conjunto, esta tesis contribuye al desarrollo de sistemas avanzados de liberación de fármacos para el tratamiento de enfermedades neuronales y oftálmicas. Aporta valiosos conocimientos sobre el destino y la eficacia de las NC a través de las barreras mucosas y sobre el uso de hidrogeles personalizados para la administración de fármacos hidrofílicos en el segmento anterior del ojo.
Resumen (otro idioma): This thesis explores the potential of nanotechnology to enhance drug delivery systems (DDS) efficiency and target to i) the brain (Part A) and ii) the anterior segment of the eye (Part B). In this work we focused on the challenges posed by biological barriers, particularly the nasal mucosal barrier and the corneal one, which limit therapeutic agent permeation and efficacy. We developed different polymer-based nanostructures for the efficient delivery of drugs beyond such barriers. i) In Part A, nose-to-brain delivery was studied by a comprehensive exploration of the fate of polymeric-based nanocapsules (NCs) by monitoring them using the Förster Resonance Energy Transfer (FRET) phenomenon. The optimization of synthesis and substitution strategies results in stable FRET-NCs with potential applications in drug delivery and cellular tracking. Chapter 1 also establishes a surrogate model of nasal mucosal epithelium using Calu-3 cells, allowing for the investigation of NC fate and interactions. Balb/c cells were used as target cells and placed on the opposing side of the barrier to prove the potential of these CCs for drug delivery and cellular internalization after barrier crossing. ii) Simultaneously, in Part B, a polymeric-based formulation for the ophthalmic administration of a hydrophilic compound has been developed as part of a collaborative project with the company Casen Recordati. Chapter 2 explores the encapsulation of hydrophilic APIs using single, double-emulsion-based NCs and nanogels. While the formers revealed poor loading and stability, polymeric nanogels, particularly alginate nanogels (AGNs), demonstrated promising results with higher drug loading and stability, making them potential candidates for ophthalmic drug delivery. In Chapter 3, a hydrogel formulation is proposed to achieve a more effective treatment of ophthalmic diseases. API delivery is proposed by using i) commercial and ii) customized hydrogels. i) The co-encapsulation of the API and vitamin E (VE) in conventional and silicone-based commercial contact lenses (CLs) is achieved using different loading strategies. Silicone-based CLs exhibit sustained release profiles, making them preferable for therapeutic delivery to the cornea. ii) The fabrication of API-loaded polyvinyl alcohol-based nanowafers (NWs) revealed the sustained release of the API and protective effects against its oxidation. Both different crosslinking strategies and loading approaches have been explored to control NW solubility and to improve API delivery. In vivo experiments showed promising results in increasing the persistence of NWs, highlighting their potential for an extended-release duration. Overall, this thesis contributes to the development of advanced drug-delivery systems for the treatment of neuronal and ophthalmic diseases. It provides valuable insights into the fate and efficacy of NCs across mucosal barriers and to the use of customized hydrogels for the delivery of hydrophilic drugs to the anterior segment of the eye.
Resumen (otro idioma): This thesis explores the potential of nanotechnology to enhance drug delivery systems (DDS) efficiency and target to i) the brain (Part A) and ii) the anterior segment of the eye (Part B). In this work we focused on the challenges posed by biological barriers, particularly the nasal mucosal barrier and the corneal one, which limit therapeutic agent permeation and efficacy. We developed different polymer-based nanostructures for the efficient delivery of drugs beyond such barriers. i) In Part A, nose-to-brain delivery was studied by a comprehensive exploration of the fate of polymeric-based nanocapsules (NCs) by monitoring them using the Förster Resonance Energy Transfer (FRET) phenomenon. The optimization of synthesis and substitution strategies results in stable FRET-NCs with potential applications in drug delivery and cellular tracking. Chapter 1 also establishes a surrogate model of nasal mucosal epithelium using Calu-3 cells, allowing for the investigation of NC fate and interactions. Balb/c cells were used as target cells and placed on the opposing side of the barrier to prove the potential of these CCs for drug delivery and cellular internalization after barrier crossing. ii) Simultaneously, in Part B, a polymeric-based formulation for the ophthalmic administration of a hydrophilic compound has been developed as part of a collaborative project with the company Casen Recordati. Chapter 2 explores the encapsulation of hydrophilic APIs using single, double-emulsion-based NCs and nanogels. While the formers revealed poor loading and stability, polymeric nanogels, particularly alginate nanogels (AGNs), demonstrated promising results with higher drug loading and stability, making them potential candidates for ophthalmic drug delivery. In Chapter 3, a hydrogel formulation is proposed to achieve a more effective treatment of ophthalmic diseases. API delivery is proposed by using i) commercial and ii) customized hydrogels. i) The co-encapsulation of the API and vitamin E (VE) in conventional and silicone-based commercial contact lenses (CLs) is achieved using different loading strategies. Silicone-based CLs exhibit sustained release profiles, making them preferable for therapeutic delivery to the cornea. ii) The fabrication of API-loaded polyvinyl alcohol-based nanowafers (NWs) revealed the sustained release of the API and protective effects against its oxidation. Both different crosslinking strategies and loading approaches have been explored to control NW solubility and to improve API delivery. In vivo experiments showed promising results in increasing the persistence of NWs, highlighting their potential for an extended-release duration. Overall, this thesis contributes to the development of advanced drug-delivery systems for the treatment of neuronal and ophthalmic diseases. It provides valuable insights into the fate and efficacy of NCs across mucosal barriers and to the use of customized hydrogels for the delivery of hydrophilic drugs to the anterior segment of the eye.
Pal. clave: biología celular ; cultivo celular ; tecnología de materiales ; química farmacéutica
Titulación: Programa de Doctorado en Bioquímica y Biología Molecular
Plan(es): Plan 485
Área de conocimiento: Ciencias
Nota: Presentado: 24 05 2024
Nota: Tesis-Univ. Zaragoza, , 2024
Aportación del TFG/M a la Sostenibilidad: Garantizar una vida saludable y promover el bienestar para todos y todas en todas las edades
Fecha de embargo : 2026-05-24
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