Delivery of Chemically Modified Peptides and Proteins through the Blood-Brain Barrier

Peptide- and protein-based signal substances serve important functions in our body. Neuropeptides are a class of neurotransmitters involved in specific communication in the peripheral and central nervous system. Therefore, natural and synthetic neuropeptides have potential significance as neuropharmaceuticals. Monoclonal antibodies (MAb) represent another type of proteins which can be used potentially as diagnostic or therapeutic agents. However, the poor permeability of peptides and proteins through biological membranes (e.g. cell membranes) is among the principal reasons, why these compounds have not yet gained the significance as neuroactive drugs in practice which theoretically could be expected from their bioactivity. The blood-brain barrier (BBB) consists of tightly sealed cell membranes and prevents the free access of large and/or hydrophilic substances from blood to brain. There are, however, active uptake systems for some endogenous peptides and proteins present at the BBB, which may be exploited in a physiological approach of drug delivery to the brain. After an introduction to the physiology of the BBB, an overview of potential strategies of drug delivery is given. The physiological approach is presented with examples, showing how peptides and proteins can be modified to achieve pharmacologically significant brain concentrations after systemic administration