In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide, vectorized against amyloid plaques and potentially able to cross the blooda??brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging

摘要

Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10a??years after its onset and development. It is characterized by the accumulation of amyloida???2 peptide (ABP) into amyloid plaques between nerve cells, which produces a massive local neurodegeneration. Molecular magnetic resonance imaging allows diagnosis of AD by showing ABP accumulation in the brain. The ultrasmall particles of iron oxide (USPIO) derivatives proposed in the present work were functionalized with peptides that present an affinity for ABP, independently of its state of aggregation. Their nanomolar Kd* confirms the high affinity of our vectorized contrast agents (VCA) for ABP and therefore their high labeling potential, specificity and sensitivity. Their lack of toxicity has been demonstrated, both by in vitro studies using the MTT method on several cell types, and by in vivo investigations with assessment of renal and hepatic biomarkers and by histopathology evaluation. The results of biodistribution studies corroborated by MRI demonstrate that USPIOa??PHO (USPIO coupled to peptide Ca??IPLPFYNa??C) are able to cross the blooda??brain barrier without any facilitating strategy, and accumulates in the brain 90a??min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIOa??PHO seems to have a genuine potential for labeling amyloid plaques in the brain; it has a nanomolar binding affinity, no toxic effects, and its elimination halfa??life is about 3a??h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA. Copyright ?? 2014 John Wiley & Sons, Ltd.