**3. The EPR effect and endocytosis of polymer-drug conjugates**

Anticancer polymer-drug conjugates can be divided into two targeting modalities: passive and active. While clinical anticancer activity has been achieved by passive macromolecular drug delivery systems, further selectivity is possible by active targeting (Luo & Prestwich, 2002). Polymer-drug conjugates can promote passive tumor targeting by EPR effect and allow for lysosomotropic drug delivery following endocytic capture of the drugs (Greco & Vicent, 2008).

The view that the polymer-drug conjugates passively accumulate in tumor tissues because EPR effect is clearly supported by the electron microscopic observation that the peripheral tumor vascular endothelium has quantitatively more fenestrations and open junctions than normal vessels (Li, 2002; Roberts & Palade, 1997). Tumor vasculature is more permeable to macromolecules than normal vasculature because the structures between the neovasculature in tumors and the mature vasculature in normal organs are different (Roberts & Palade, 1997; Singer, 2005). The paucity of lymphatic vessels in tumor tissues allows the retention of these macromolecules in the interstitial space, which leads to 10 to 100-fold increase in intratumoral drug concentrations for a prolonged time when compared with an equivalent dose of the anticancer drug given according to the conventional methods.

The phenomenon of EPR effect is applicable for almost all rapidly growing solid tumors and it has been widely used in cancer-targeting drug design (Iyer et al., 2007; Maeda et al., 2000; Reddy, 2005). The EPR effect is molecular weight (MW) - and size-dependent and is most effective with agents whose MWs are 50 000 or greater, which is above the threshold for renal excretion. Due to the different pathways to enter the cells between the small molecule drugs and the macromolecule drugs, multi-drug resistance (MDR) can be minimized at the same time (Boddy et al., 2005; Greish et al., 2003; Shaffer et al., 2007). Because of the stronger metabolic activity of the cancer cells, in addition to the EPR effect, cancer cells show a higher degree of uptake of macromolecules by endocytosis than normal cells (Li, 2002). The process of EPR and endocytosis is illustrated in Fig. 2.
