ABSTRACT

Although a large body of studies supports chelating agents as a potential multifunctional therapeutic approach to prevent and treat AD, the diffi culties presented by bi-directional crossing of the BBB and the potential toxicity of the currently available chelators hamper further studies. In fact, however, these obstacles may be overcome by utilizing nanoparticle delivery technology, which has shown promise in brain targeting, improved drug effi cacy and reduced drug toxicity (Kreuter 2001; Kreuter et al. 2002). Although the mechanisms by which the nanoparticles penetrate BBB are not fully known, there are several possibilities that likely work in combination to achieve the desired effect (Bonda et al. 2011). For example, (1) increasing retention of nanoparticles in bloodbrain capillaries combined with absorption into capillary walls to create a higher concentration gradient, enhances nanoparticle transport across endothelial cell layers into the brain; (2) a surfactant effect that would lead to membrane fl uidization and/or to opening tight junctions between endothelial cell, thus enhancing drug permeability; (3) an inhibition of the effl ux system (i.e., P-glycoprotein) via polysorbate-80 (a nanoparticle coating proven to yield the most effective delivery of drugs across the BBB (Alyautdin et al. 1998; Kreuter et al. 2002; Schroeder et al. 1998)); (4) endocytosis and/or transcytosis through the BBB. While each of these mechanisms is quite possible, the most probable one seems to be the receptor-mediated endocytosis of the nanoparticles.