ABSTRACT
The treatment of brain diseases is particularly challenging because of the blood-brain barrier (BBB) (1-3). Generally, only low molecular weight, lipid-soluble molecules and a few peptides and nutrients can cross the BBB to a notable extent, either by passive diffusion or via specific transport mechanisms. Thus, for most drugs it is very difficult to achieve therapeutic levels within the brain tissue via the common administration routes (e.g. intravenous, intramuscular, subcutaneous, or oral). In addition, highly potent drugs (e.g. anticancer drugs and neurotrophic factors) that may be necessary to be delivered to the central nervous system (CNS) often cause serious toxic side effects when administered systemically. To overcome these restrictions, three major approaches have been proposed (2):
(1) The drug is chemically modified in order to enhance its BBB permeability or is linked to a carrier which is capable to cross this barrier. For example, two more lipophilic derivatives of the anticancer drug carmustine (lomustine and semustine) have been synthesized to increase the resulting brain tissue concentration and, thus, the efficiency of CNS tumor treatments. Unfortunately, clinical trials with these more lipophilic derivatives did not show any significant advantage compared to carmustine administration (4). A comprehensive overview on vector-mediated drug delivery to the brain has been given by Pardridge (5). For example, certain monoclonal antibodies undergoing receptor-mediated transcytosis through the BBB can successfully be used to delivery drugs to the target tissue.
