A D-peptide ligand of neuropeptide Y receptor Y₁ serves as nanocarrier traversing of the blood brain barrier and targets glioma

Diseases of the central nervous system (CNS) are challenging for drug treatment because the blood-brain barrier (BBB) restricts entry of drugs into the brain tissue. Therefore, strategies for drug transport across the BBB are an important component in development of CNS drug therapies. Here, a D-amino acid ligand of the neuropeptide Y (NPY) receptor Y₁ is described, ^D [Asn²⁸, Pro³⁰, Trp³²]- ^DNPY (25−36) (termed ^DAPT), with 2.5 times higher number of hydrogen bonds interacting with the receptor, based on docking into a structural model, than the corresponding peptide with standard L-amino acids (^LAPT). Using in vitro BBB models, in vivo healthy mice with intact BBB, and U87-MG orthotopic tumor-bearing mice, we demonstrate that ^DAPT exhibits significantly higher ability than ^LAPT to serve as nanocarrier across the BBB and specifically targets gliomas. Using ^DAPT nanomicelles loaded with IRDye780, it was possible to achieve excellent photothermal therapeutic and photoacoustic cancer imaging. Thus, this study demonstrates the importance of ligand stability and affinity in Y₁ receptor-mediated transcytosis and paves the way for versatile brain tumor imaging and therapy using nanomicelles.