Development of an LDL receptor-targeted peptide susceptible to facilitate the brain access of diagnostic or therapeutic agents

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 strategies (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 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 is able to bind the ED-LDLR in the presence of natural ligands and dissociates at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide is endocytosed by endothelial cells by the caveolae-dependent pathway, preventing its degradation and suggesting its transcytosis. The in vivo studies performed by Magnetic Resonance Imaging and Fluorescent Lifetime Imaging suggest the brain penetration of this ED-LDLR-targeted peptide.