Challenge and progress in delivering molecules to the brain

Title : Challenge and progress in delivering molecules to the brain

Abstract:

One of the major challenges in studying brain function and diseases (i.e., Alzheimer’s, Parkinson’s, multiple sclerosis (MS), and brain tumors) lies in the difficulty in delivering molecules to the brain. The critical obstacle in vivo is the presence of the blood-brain barrier (BBB). In addition, a very large portion (98%) of currently available drugs to treat diseases cannot be used to treat brain diseases. The long-term goal is to develop novel methods to analyze the chemical, cellular, and extracellular components of the brain to determine their functions in normal and brain-diseased animals. The short-term goal of this project is to deliver peptides and proteins with imaging labels that can be used to detect changes in the brains of animal models of brain diseases such as Alzheimer’s, MS, and brain tumors. The central hypothesis is that modulating cadherin-mediated cell-cell adhesion in the BBB using HAV and ADT peptides can enhance the paracellular permeation of small-to-large molecules through the BBB. The results showed that cadherin peptides (i.e., HAV- and ADT-peptides) increase the in vivo brain delivery of drugs (camptothecin), paracellular marker molecules (14C-mannitol, gadopentetic acid (GdDTPA), 3 H-PEG, and 25 kDa IRdye800cw-PEG), efflux pump substrates (rhodamine 800 (R800), 3 H-daunomycin), 8–12 amino acid peptides (i.e., cIBR7 and cLABL), and proteins (i.e., 65 kDa Gd-DTPA-albumin (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 animal models of brain diseases. 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. Using NMR spectroscopy and molecular modeling, 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.

Biography:

Professor Teruna Siahaan earned a B.S. and an M.S. from the University of Indonesia and a Ph.D. from the University of Arizona. He completed a postdoctoral fellowship at the University of California, Santa Barbara. His research interests are in the utilization and modulation of cell adhesion molecules on the cell surface for targeted drug delivery to a specific cell type and for enhancing drug permeation through the intestinal mucosa and blood-brain barrier (BBB). Dr. Siahaan’s group is using E-cadherin peptides to enhance permeation of large hydrophilic molecules (i.e., peptides and proteins) through the intestinal mucosa and BBB. The hypothesis is that E-cadherin peptides modulate the E-cadherin interactions at the intercellular junctions to create larger openings that will allow paracellular permeation of large hydrophilic molecules (e.g., peptides and proteins). His group is also using peptides derived from cell adhesion molecules (i.e., ICAM-1 and LFA-1) to target drugs to leukocytes and vascular endothelial cells in inflammatory and autoimmune diseases (i.e., rheumatoid arthritis). Cell adhesion peptides are being used to target antigenic peptides (i.e., bi-functional peptide inhibitor (BPI)) to block the formation of the immunological synapse at the interface between T cells and antigen presenting cells (APC). BPI molecules have been shown to suppress autoimmune disease models such as multiple sclerosis, type-1 diabetes and rheumatoid arthritis.