ABSTRACT
Although clinically useful, passive targeting strategies suffer from several limitations. A vast majority of nanoparticles utilize a surface coating of PEG for biocompatibility; however, this hydrophilic surface hampers endosomal escape and intracellular uptake of the carriers into tumor cells creating the so-called “PEG dilemma”(Hatakeyama et al., 2011). Furthermore, it is not possible to ubiquitously target cells within a tumor due to limitations imposed by inefficient diffusion for certain drugs. This makes the passive targeting approach difficult to control, which could lead to multiple-drug resistance (MDR) (Peer et al., 2007). Overexpressed transporter proteins on the cancer cell surface expel drugs to lower their therapeutic effect, causing cancer cells to become resistant to a variety of drugs (Gottesman et al., 2002). Additionally, the inherent heterogeneity within tumors further complicates passive targeting (Jain, 1994). Active targeting of nanocarriers can overcome the limitations imposed by passive targeting and can provide specific target recognition to nanocarriers (Peer et al., 2007; Torchilin, 2009). 14.3.2 Active TargetingActive targeting relies on the modification of nanoparticles with specific ligands on their surface that will be recognized by molecules selectively or differentially expressed on the tumor cells (Torchilin, 2006a; Kamaly et al., 2012). It enables preferential accumulation of nanoparticles in the tumor tissue, individual tumor cells, or intracellular organelles inside the cells (Nie et al., 2007). The binding of ligands to receptors allows internalization of nanoparticles via receptor-mediated endocytosis (Chou et al., 2011). Active targeting can be combined with the ability of the nanocarrier to circulate for longer times by decorating the surface of PEGylated nanocarriers with targeting ligands, a strategy that can improve the intracellular uptake and selectivity compared to non-targeted PEGylated carriers (Hatakeyama et al., 2011; Torchilin, 2006a). Targeting ligands can be attached to nanocarriers via the PEG spacer arm so as to extend the ligand outside the dense PEG brush and avoid steric hindrance for its binding to target receptors (Torchilin et al., 2001a; Torchilin, 2009). A number of ligands have been investigated to date for active targeting of various nanocarriers, as mentioned in Section 14.2.
