A D-Peptide Ligand of Nicotine Acetylcholine Receptors for Brain-Targeted Drug Delivery

Lysosomes of brain capillary endothelial cells are implicated in nicotine acetylcholine receptor (nAChR)-mediated transcytosis and act as an enzymatic barrier for the transport of peptide ligands to the brain. A D-peptide ligand of nAChRs (termed (CDX)-C-D), which binds to nAChRs with an IC50 value of 84.5nM, was developed by retro-inverso isomerization. (CDX)-C-D displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an invitro blood-brain barrier monolayer compared with the parent L-peptide. When modified on liposomal surface, (CDX)-C-D facilitated significant brain-targeted delivery of liposomes. As a result, brain-targeted delivery of (CDX)-C-D modified liposomes enhanced therapeutic efficiency of encapsulated doxorubicin for glioblastoma. This study illustrates the importance of ligand stability in nAChRs-mediated transcytosis, and paves the way for developing stable brain-targeted entities.