Factors Controlling Pharmacokinetics of Intravenously Injected Nanoparticulate Systems

Abstract

Particulate nanosystems, such as liposomes, polymeric micelles, and nanospheres have long been used for site-specific delivery of therapeutic and diagnostic agents following intravenous injection (Moghimi et al., 2005a). Additionally, there is a catalogue of nanoparticulate entities exhibiting unique physical and chemical properties, such as high rigidity, high thermal and electrical conductivity, and superparamagnetism, which have applications in experimental imaging, cell ablation, and even drug delivery following introduction into the vasculature (Moghimi et al., 2005a; Moghimi & Kissel, 2006). Examples include semiconductive singleand multi-walled carbon nanotubes (SWNT and MWNT, respectively) and iron/iron oxide core–shell nanoclusters (Klumpp et al., 2006; Qiang et al., 2006). The biological performance of intravenously injected nanoparticles is controlled by a complex array of physicochemical and physiopathological factors (Moghimi et al., 2001, 2005a, 2006c). Physicochemical considerations include nanoparticle size distribution, shape, density, rigidity or deformability, and surface characteristics (e.g. surface electric charge, surface density, and conformation of adsorbed or grafted synthetic polymers and biological ligands). These factors not only control the flow properties of nanoparticles within the blood vessels and at bifurcations in vascular and capillary systems, but also modulate nanoparticle circulation times, tissue deposition patterns, mode of entry into cells (as in Rho-dependent phagocytosis, clathrin-mediated endocytosis, internalization through membrane rafts, and uptake mechanisms independent of phagocytosis, clathrin, and caveolae), intracellular trafficking, contents release, and toxicity (Andresen et al., 2004; Bhatia et al., 2003; Decuzzi & Ferrari, 2006; Harush-Frenkel et al., 2007; Lovric et al., 2005; Moghimi et al., 2001, 2004, 2005a, 2006c; Patil et al., 2001; Poznansky & Juliano, 1984). For instance, oblate ellipsoidal particles have been proposed to adhere more effectively to the biological substrates than their corresponding classical spherical particles of the same volume (Decuzzi & Ferrari, 2006). In addition, non-spherical nanoparticles can carry more drugs and