Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier

Article type: Research Article

Authors: André, Séverine^a | Ansciaux, Emilie^{a; 1} | Saidi, Elamine^a | Larbanoix, Lionel^b | Stanicki, Dimitri^a | Nonclercq, Denis^c | Vander Elst, Luce^a | Laurent, Sophie^{a; b} | Muller, Robert N.^{a; b} | Burtea, Carmen^{a; *}

Affiliations: [a] Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium | [b] Center for Microscopy and Molecular Imaging, Gosselies, Belgium | [c] Laboratory of Histology, University of Mons, Mons, Belgium

Correspondence: [*] Correspondence to: Professor Carmen Burtea, Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium. Tel./Fax: +32 65373524; E-mail: [email protected].

Note: [1] Present address: Bone Therapeutics, Gosselies, Belgium.

Abstract: The diagnosis of Alzheimer’s disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls’-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

Keywords: Alzheimer’s disease, amyloid-β peptide, blood-brain barrier, contrast agents, functionalized iron oxide nanoparticles, magnetic resonance imaging

DOI: 10.3233/JAD-170563

Journal: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1547-1565, 2017