Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents
Séverine André,
Lionel Larbanoix,
Sébastien Verteneuil,
Dimitri Stanicki,
Denis Nonclercq,
Luce Vander Elst,
Sophie Laurent,
Robert N. Muller,
Carmen Burtea
Affiliations
Séverine André
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Lionel Larbanoix
Center for Microscopy and Molecular Imaging, rue Adrienne Bolland 8, B-6041 Gosselies, Belgium
Sébastien Verteneuil
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Dimitri Stanicki
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Denis Nonclercq
Department of Histology, University of Mons, Pentagon—1B, Avenue du Champ de Mars 6, B-7000 Mons, Belgium
Luce Vander Elst
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Sophie Laurent
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Robert N. Muller
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Carmen Burtea
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Avenue Maistriau 19, Mendeleïev Building, B-7000 Mons, Belgium
Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.
