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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10 years after its onset and development. It is characterized by the accumulation of amyloid-β 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 USPIO-PHO (USPIO coupled to peptide C-IPLPFYN-C) are able to cross the blood-brain barrier without any facilitating strategy, and accumulates in the brain 90 min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIO-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 half-life is about 3 h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA.

Are iron oxide nanoparticles safe? Current knowledge and future perspectives

“…Moreover, no systemic distribution of Fe 2 O 3 nanoparticles or significant changes in toxicity parameters were observed in Sprague-Dawley rats orally administered, daily over a 13-week period [99]. Ansciaux et al [107] functionalized several ultrasmall iron oxide particles with peptides that present an affinity for amyloid-␤ peptide, for being used in early diagnosis of Alzheimer's disease. The particles coupled to peptide C-IPLPFYN-C demonstrated ability to cross the blood-brain barrier in mice without any facilitating strategy, and accumulated in brain 90 min after their intravenous injection.…”

Application of Iron Oxide Nanoparticles in the Diagnosis and Treatment of Neurodegenerative Diseases With Emphasis on Alzheimer’s Disease

“…Since there are iron deposits in the amyloid plaques, in T2-and T2 * -weighted MR images, the plaques showed a hypointense signal (Chamberlain et al, 2009). Thus, with the help of specific MRI sequences, the detection of amyloid plaques can use not the CAs but the iron content (Ansciaux et al, 2015). Since the detection of iron relies on the nature properties of the amyloid plaques and the stage of the disease (larger plaques contain higher amounts of iron, which makes the detection easier), it normally requires greater than 7-T magnetic field and several hours as acquisition time (Ansciaux et al, 2015).…”

“…Thus, with the help of specific MRI sequences, the detection of amyloid plaques can use not the CAs but the iron content (Ansciaux et al, 2015). Since the detection of iron relies on the nature properties of the amyloid plaques and the stage of the disease (larger plaques contain higher amounts of iron, which makes the detection easier), it normally requires greater than 7-T magnetic field and several hours as acquisition time (Ansciaux et al, 2015). In AD transgenic mice, the levels of iron were high in thalamic plaques and low in cortical/hippocampal plaques, and by using different MRI sequences, the visibility of plaques in the cortex/hippocampus was different from those in the thalamus .…”

“…Another research suggested that after introducing several magnetic CAs in AD transgenic mice to detect amyloid plaques, the USPIONs were able to commendably identify transgenic mice to the wild type by detecting amyloid plaques T2 * -weighted in MRI (Yang et al, 2011b). Ansciaux et al (2015) reported that a USPIO-PHO (USPIO coupled to peptide C-IPLPFYN-C) could cross the BBB of NMRI mice by intravenous injection and accumulates in the brain for 90 min, with high affinity (nanomolar binding affinity) and low toxicity. The half-life of USPIO-PHO was about 3 h. These MRI and histochemistry studies showed that USPIO-PHO had the potential to label amyloid plaques in the brain (Ansciaux et al, 2015).…”

“…Ansciaux et al (2015) reported that a USPIO-PHO (USPIO coupled to peptide C-IPLPFYN-C) could cross the BBB of NMRI mice by intravenous injection and accumulates in the brain for 90 min, with high affinity (nanomolar binding affinity) and low toxicity. The half-life of USPIO-PHO was about 3 h. These MRI and histochemistry studies showed that USPIO-PHO had the potential to label amyloid plaques in the brain (Ansciaux et al, 2015). Sillerud et al (2013) synthesized an anti-AβPP antibody-conjugated SPION, which can cross the BBB and act as an in vivo CA for MRI of Aβ plaques in AD.…”