Title : A novel method to deliver therapeutic and diagnostic molecules to the brain
One of the major challenges in studying brain function and diseaseslies in the difficulty in deliveringmoleculesto the brain due to the presence of the blood-brain barrier (BBB). This project is aimed at developing a novel and effective method to deliver molecules to the brain for analyzing the molecular and cellular levels of brain functions in normal and brain-diseased animals (Alzheimer’s, multiple sclerosis, and brain tumors animal models). The central hypothesis is thatcadherin peptides(HAV and ADT) modulate cell-cell adhesion in the intercellular junctions of the BBB to enhance paracellular permeation of small-to-large molecules through the BBB. The results showed that cadherin peptidesincrease the in vivo brain delivery of drugs (camptothecin), paracellular marker molecules (C-mannitol, gadopentetic acid), H-PEG, and 25 kDa IRdye800cw-PEG), efflux pump substrates (rhodamine 800 (R800), H-daunomycin), 8–12 amino acid peptides (i.e., cIBR7 and cLABL), and proteins (i.e., 65 kDa galbumin) in mice and rats. These results strongly support the possibility of using cadherin peptides for non-invasive delivery of various molecules for diagnostic or therapeutic purposes to the brains of brain diseased animal models.The HAV and ADT peptides are non-toxic, and they can safely modulate the BBB for a short period to allow BBB penetration of large proteins. We also found that ADT and HAV peptides bind to the EC1 domain of E-cadherin at different binding sites.In summary,our work is the first to show that modulating cell-cell adhesion can safely increase the delivery of molecules to the brain in living mice and rats. The concept of modulating cell-cell adhesion of the BBB to improve delivery of molecules to the brain is novel and would have a broad impact on the diagnosis and treatment of brain diseases.