Seite - (000367) - in Biomedical Chemistry: Current Trends and Developments

and reproduced with permission from (Lammers, 2012). Abbreviation: EPR, enhanced permeability and retention. 3.5.3.1 Passive Targeting 3.5.3.1.1 The Fundamentals of Passive Targeting and the EPR Effect The accumulation of drug molecules and nanosystems in certain target tissues, relying exclusively on their pathophysiological features (i.e., not involving any ligand-driven mechanism), can be referred as “passive targeting” (Arias, 2011; Jhaveri, 2014). The majority of nanoparticulate systems with the size ranging between ~10–500 nm present the capability of exploiting the unique intrinsic characteristics of the tumor microenvironment, and eventually accumulating at the tumor (Torchilin, 2011). The rationale behind the preferential distribution of nanoparticles to malignant tissues, after intravenous administration, has been intensively investigated and, nowadays, it is well recognized that such behavior relies on the EPR effect (Fang, 2011; Maeda, 2001; Maeda, 2000; Matsumura, 1986; Torchilin, 2011). Contrarily to what happens in normal tissues, the microvasculature of solid tumors is characterized by a low degree of differentiation, a discontinuous highly-fenestrated endothelium and a disrupted basal membrane, essentially resulting from an active angiogenesis stimulated by a frenetic and metabolically demanding tumor growth (Carmeliet, 2000; Jain, 1998; 2010). The interendothelial fenestrations of this imperfect vascular architecture result in an increased permeability and consequent lower resistance to the extravasation selective accumulation of nanoparticles and active macromolecules from the blood vessels lumen to the tumor extravascular space (Fig. 3.5.7A) (Danquah, 2011). Additionally, the tumor tissues exhibit a compromised lymphatic drainage function, hindering the renewal of the interstitial fluid and, consequently, an effective clearance of the extravased nanoparticles leading to their accumulation in the tumor interstitium (Padera, 2004). The aforementioned pathophysiological phenomena occurring in the tumor milieu represent the fundamentals of the EPR effect, and consequently, of the EPR effect-driven passive targeting of nanosystems