Sphingomyelin-based nanoprobes as theranostic agents for atherosclerosis

• Autores: María Muñoz Hernando
• Directores de la Tesis: Jacob Fog Bentzon (dir. tes.), Fernando Herranz Rabanal (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 220
• Títulos paralelos:
  • Nanosondas que contienen esfingomielina como agentes teranósticos para la aterosclerosis
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Objective: The clinical complications of atherosclerosis constitute the leading cause of death worldwide. Current imaging techniques for the diagnosis of atherosclerosis have not shown to be very effective in detecting early-stage progressive lesions or identifying high-risk plaques. Nanoparticles have emerged as promising tools for the non-invasive molecular imaging and treatment of atherosclerosis. It has been demonstrated that enzymes that aggregate LDL are particularly important for disease activity in established plaques. Among the different arterial enzymes, SMase has been shown to be of high importance in atherosclerosis progression. Therefore, during this work we hypothesised that SMase could be used as a biomarker to develop atherosclerosis-targeted theranostic nanoprobes, expanding the library of markers that can be used for the in vivo characterisation of the disease. Approaches: In this thesis, we synthesised and comprehensively characterised two different nanoprobes based on: sphingomyelin nanomicelles with a core of iron oxide nanoparticles (SPHIONMs) and sphingomyelin solid lipid nanoparticles (SPH-SLNPs). We investigated if the nanoprobes were able to accumulate in established murine atherosclerotic plaque using ex vivo confocal microscopy and TEM imaging. We also studied the role of SMase in the accumulation process by a colocalisation analysis. The developed nanoparticles were tested as molecular imaging probes for atherosclerosis visualisation. SPHIONMs were used in T2- weighted MRI, and SPH-SLNPs were used for PET imaging. In addition, SPH-SLNPs were loaded with everolimus, to act as drug delivery agents for the targeted delivery of this drug into atherosclerosis lesions. The effect of the everolimus-loaded SPH-SLNPs was compared to that of the free drug. Aortic roots from treated mice were analysed for plaque size, and cellular composition. Results and Conclusions: We demonstrated that both the synthesis of SPHIONMs and SPH-SLNPs yielded colloidally stable nanoparticles in a reproducible manner. Confocal microscopy images showed that both nanoprobes accumulated in the atherosclerotic plaque, and that the accumulation pattern colocalised with that of SMase. T2-weighted MRI suggested the presence of SPHIONMs in atherosclerotic plaques, which was confirmed by TEM imaging. SPH-SLNPs were used as biological vectors targeting atherosclerosis which we used to develop a pretargeting approach with 68Ga-IONPs as the nanoradiotracer. Atherosclerosis visualisation with PET imaging using this method was successful. SPH-SLNPs were efficiently loaded with everolimus. Plasma lipid measurements showed that the loaded SPH-SLNPs decreased the hypercholesterolemia and hypertriglyceridemia produced by the free drug. Results from the analysed plaque features showed that empty SPH-SLNPs produced proatherogenic effects, which everolimus-loaded SPH-SLNPs trended to reduce