ABSTRACT

Most diseases of the nervous system, cancers, and infections of the brain cannot be effectively treated due to the presence of the blood-brain barrier (BBB) that restricts the entry of undesired substances to the brain. For example, more than 98% of all potential new drugs for the treatment of central nervous system (CNS) disorders do not cross the BBB. The BBB is situated at the interface of blood and brain and its primary function is to maintain the homeostasis of the brain. The human BBB has a total blood vessel length of approximately 650 km and an estimated surface area of approximately 20 m2. It is considered the most important barrier to solutes reaching the brain (Pardridge 1999). In recent years, pharmaceutical companies have focused on the development of small drug molecules as therapeutic moieties. In general, small molecules should be lipid-soluble and have a molecular weight below 400-600 Dalton to be able to cross the BBB in therapeutically effective quantities (Pardridge 1999). The BBB is formed by a network of closely sealed endothelial cells in the brain’s capillaries (Fig. 1), and it expresses a high level of proteins that pump foreign molecules away from the brain. Therefore, even small drug molecules cannot cross the BBB in suffi cient quantities without brain drugtargeting strategies. Meanwhile, more and more larger molecules have been generated by biotechnological means which constitute promising alternatives for the treatment of diseases of the CNS. These include proteins (neurotrophins) (Pardridge 2002) and genes (neprylysin gene) for Alzheimer’s Disease, antisense therapy for Huntington’s Disease and monoclonal antibodies for diagnostic purposes and treatment of brain metastasis of breast cancer tumors. These macromolecules cannot cross the BBB without using targeting and delivery strategies. Receptors on the brain’s capillary endothelial cells for insulin, insulin-like growth factor

(IGF), leptin, low-density density lipoprotein (LDL) and transferrin (Tf), allow some molecules, such as glucose, transferrin and insulin (which are necessary for brain homeostasis) to cross the BBB via specifi c pathways (Roberts et al. 1993). Ligand-receptor mediated drug delivery has received major attention in the past few years owing to the potential of site-specifi c crossing of the BBB therefore allowing delivery to the brain of drugs bound to a specifi c ligand. Among the ligands used to cross the BBB, transferrin (Tf) has been widely applied in the active targeting of anticancer agents, proteins and genes, as well as to proliferating malignant cells in the brain which also over-express transferrin receptors (Prior et al. 1990). The applications of nanoparticles (NPs) in biomedicine, as controlled drug delivery and drug targeting vehicles, have been widely studied and rapidly advanced in the last twenty years (Cao 2004). In this chapter, we present an overview of the studies using nanoparticulate vectors to target the brain with the transferrin receptor as a target (Fig. 2).