ATPS-87DEVELOPMENT AND IN VIVO VALIDATION OF BLOOD-BRAIN BARRIER TARGETING PEPTIDES

Abstract

Blood-brain barrier (BBB) is a major barrier to delivering drugs to the brain parenchyma. Affinity carriers able to cross BBB would allow delivery drugs for the treatment of neurological diseases such as multiple sclerosis, Huntington's, Parkinson's and Alzheimer's. In the presence of brain tumors the BBB is locally disrupted, however, the infiltrative glioma cells distant from the tumor core hide behind intact BBB beyond the reach of anticancer therapies. Thus, the activity of brain cancer drugs would be potentiated by carriers that facilitate BBB penetration. Here, we used in vivo T7 phage display of cyclic CX7C peptide libraries on healthy Balb/C mice to identify peptides that home to brain upon systemic administration. In vivo biopanning in combination with deep sequencing of peptide-encoding phage genomic DNA and bioinformatics analyses led to identification of a peptide-phage clone that selectively homes to normal brain. Tested as an individual phage clone, the phage displaying the brain-homing peptide, KT1, showed about 50 times higher brain tropism compared to insertless control phage. In vivo alanine scan was used to map the residues that are critical for KT1 brain homing. Our ongoing work deals with elucidating the mechanism of KT1 recruitment to brain microvessels and evaluation of its potential as a BBB penetrating agent. We are also evaluating KT1 as a ligand for targeting drugs and imaging agents to glioblastomas, especially to the infiltrative guerilla glioma cells.