**3. Nanocarrier-mediated CNS delivery of diagnostic and therapeutic agents**

Drug delivery across the BBB requires knowledge of both "barrier" and permeability properties of the brain endothelial cells. Transport across BBB may involve simple diffusion, facilitated diffusion, diffusion through aqueous pores, and active transport through protein carriers. In case of simple diffusion solute molecules travels along concentration gradient. Facilitated diffusion involves binding with specific membrane-traversing protein, coupled with movement along the concentration gradient. Charged ions and solutes cross the BBB by diffusion through aqueous pores. Active transport of solutes through protein carrier against concentration gradient involves expenditure of ATP. The presence of large number of mitochondria in the endothelial cells is thought to provide the required energy in form of ATP [15]. This mechanism involves an alteration in the affinity of a carrier for the solute molecules as it travels across the BBB. While designing nanocarrier mediated CNS delivery, transporter systems involved in ferrying essential molecules such as glucose are of utmost importance. These systems can be employed for delivery of potential nanotheranostics across the BBB. There are five types of sodium-independent glucose transporters (GLUT) which transport 2-deoxyglucose, 3-O-methylglucose, mannose, galactose and glucose across the BBB. The most important being 45–55 kDa glycosylated protein GLUT-1. It is mostly present in endothelial cells of arterioles, venules and capillaries, wherein it facilitates movement of D-glucose from the peripheral circulation into the brain. Other worth mentioning glucose transporters are GLUT-3 in brain neurons and GLUT-5 in microglial cells in the brain. They transport 2-deoxyglucose, 3-O-methylglucose, mannose, galactose and glucose across the BBB [16].

Another significant transport system that works in an analogous manner is P-glycoprotein multiple drug resistant protein (P-gp, MDR1). It has been comprehensively investigated as a possible carrier for drug delivery. This efflux transporter is usually expressed on luminal surface of endothelial cells, astrocytes and microglial cells. It prevents toxins from gaining entry into the brain parenchyma [17, 18]. Anticancer agents like Vinca alkaloids, anthracyclines, and taxanes are substrates for MDR1 are transported by Pgp. It limits their accumulation in the brain. Recently, it has been found that MDR1 regulation is altered by various disease conditions, and, in turn, diseases of the brain influence MDR1 expression [19, 20]. The presence of large number of receptors at the surface of BBB can be utilized by potential nanocarriers for enhanced brain by coupling with receptor-specific molecules or analogues. A large number of molecules such as insulin, insulin-like growth factors (IGF-1 and IGF-2), leptins, and transferrin can be transported into the brain following receptor-mediated endocytosis [13]. The nanoparticles should be designed to bypass efflux transport systems present at the luminal side (such as MDR1). Instead, nanoparticles could be substrates of transport mechanisms enhancing the passage of specific molecules like GLUT-1, IGF-1, and IGF-2 across the BBB [21].
