Nanomaterials for multimodal molecular imaging

Abstract

The development of hybrid probes for multimodal molecular imaging is changing the diagnosis and characterisation of complex pathologies. The fusion of the outstanding sensitivity of positron emission tomography (PET) and the excellent anatomical resolution of magnetic resonance imaging (MRI), provides an ideal combination of structural and anatomical information, which is key to expand the application of molecular imaging for the diagnosis of complex and multifactorial diseases. Iron oxide nanoparticles (IONPs) have been traditionally used as negative (T2) contrast agents, darkening tissues or areas in which they accumulate. However, in recent years there has been a great amount of research focusing on the production of IONPs for positive (T1) contrast MRI. One of the most appealing properties that nanoparticles usually offer is the possibility of tailoring their synthesis and functionalisation to obtain probes that generate or enhance the signal in more than one imaging modality, via incorporation of moieties in the core or the surface of the nanoparticle. In this thesis, we developed a novel microwave-assisted method for the synthesis of IONPs coredoped with the positron emitter 68Ga and with relaxometric properties suitable for hybrid T1 MRI/PET imaging. Full characterisation revealed optimal radiochemical properties for PET imaging and excellent relaxometric properties for T1 MR imaging, demonstrating that the combined use of nanotechnology and radiochemistry can render an innovative tool for the dual imaging of biological processes in vivo. Furthermore, in an attempt to improve the relaxometric properties of our IONPs, we synthesised iron oxide nanoparticles doped with different amounts of copper. This resulted in three copper-doped samples with different relaxometric properties and hence, contrast capabilities. Further MR angiography in mice revealed an outstanding candidate for T1 MRI, having relaxometric properties and contrast capabilities ameliorated with respect to undoped IONPs. In addition, this copper-doped nanoparticle sample was successfully vectorised into tumours by the bioconjugation of an integrin-binding peptide, providing a remarkable T1 contrast enhancement in T1-weighted MR imaging of tumour-bearing mice. Finally, we used our 68Ga core-doped IONPs to visualise microcalcifications in atherosclerotic plaque by PET and T1-weighted MRI. To do this, we conjugated our 68Ga core-doped IONPs with a bisphosphonate moiety to produce a surface conjugated bisphosphonate nanoparticle, named as HAPmultitag. Our nanotracer showed high affinity towards calcium salts both in vitro and in vivo, allowing us to spot microcalcifications in mice of different ages fed on high fat cholesterol diet and therefore, different plaque progression stages. To our knowledge, HAP-multitag is the first reported probe that enables not only the localisation of microcalcifications at the earliest stage but also the longitudinal characterisation of microcalcifications in atherosclerotic plaque in vivo.