Active targeting is the method in which the therapeutic agent is delivered to tumors by attaching it with a ligand that binds to specific receptors that are overexpressed on target cells. Upon binding to the receptors on the target, the particle (now conjugated with ligands) could be internalized into the cell (internalizing ligand) or remain cell-bound without being internalized (noninternalizing ligand). So, what specific receptors are overexpressed on tumor cells? They can be divided into two classes: (1) targets that are preferentially expressed on endothelial cells in tumor blood vessels (e.g., integrin-vb3 and negatively charged phospholipids) (Hood et al. 2002; Ran et al. 2002) and (2) targets that are overexpressed on tumor cells (e.g., HER2 and disialoganglioside (GD2)) (Park et al. 2002; Pastorino et al. 2003).
The sizes of drug carriers are very critical. One needs the drugs to be transported by blood to the desired site (i.e., tumor) to be taken up by the tumor cells. As previously mentioned, the endothelium of blood vessels in most healthy tissues has a pore size of 2 nm, and 6 nm pores are found in postcapillary venules (Hobbs et al. 1998; Hood et al. 2002). In contrast, the endothelium of tumor vasculature has pore sizes much greater, usually from 100 to 780 nm (Hobbs et al. 1998; Hood et al. 2002). Therefore, as illustrated in Fig. 1, particulate drug carriers of 50-100 nm size can enter the tumor from tumor blood vessels, but cannot get into healthy tissue from healthy blood vessels (Drummond et al. 1999).
Figure 2 gives an example of doxorubicin (DOX)-loaded liposome with phospholipid-anchored folic acid-PEG conjugates (FTL-Dox) accumulated on the side of KB-HiFR tumor cells in vitro (Gabizon et al. 2004). Phospholipid-anchored folic acid is the ligand to target folate receptors (FR) overexpressed on KB-HiFR tumor cells. The DOX fluorescence (orange) is readily recognized in the nucleus sparing the nucleolus.
It is clear that the above choice of nanoparticle size is part of passive targeting when one tries to avoid the uptake of drugs from healthy tissues. It is true that the passive component of drug targeting is important in active targeting systems and should not be overlooked when designing active targeting strategies. It is important because: (1) the majority of a living body comprises nontarget sites. Even the liver, one of the largest drug targets, is only 2% of the weight of the entire body. That is, 98% of the body can be considered to be a nontarget site in this case. As a result, when the drug reaches its target, only a fraction of the applied dose remains after nonspecific capture at nontarget sites. (2) In most cases, before specific
ligand-receptor interactions take place in active targeting, the drug-carrier-ligand complex has to be transferred through many other tissues since most targets are located in the extravascular space. Exceptions are cases for intravascular targets such as lymphocytes and vascular endothelial cells. For example, in drug applications via the bloodstream, the drug must first be transferred through the vascular endothelium followed by permeation through the interstitial space to the extravas-cular targets.
After reaching the tumor site, the drugs will be internalized (i.e., enter tumor cells) with or without internalization of the carrier, i.e., nanoparticles. In the latter, nanoparticles will stay localized in the interstitium surrounding the tumor cells, while the drug, after being released from the drug-nanoparticle conjugate during degradation, will enter tumor cells through diffusion or active transport. The factors that accelerate this degradation to release drugs are possibly the atypical condition of the tumor environment (such as acidic pH and the presence of enzymes and oxidizing agents (Drummond et al. 1999)). Many methods have taken advantage of these factors to design particulates that preferentially disintegrate at acidic pH or increased temperature (Kirpotin et al. 1996). Internalized drugs accumulate in endo-somes and then lysosomes. They can only exert pharmacological activities when they exit these organelles and reach the cytosol or the nucleus. If the nanoparticles are also internalized along with the drugs, the internal environment of lysosomes will be the factors that disintegrate the nanoparticles and the drug can then diffuse out of the lysosomes. Between these two strategies of internalizing drugs, the methods that also internalize carrier particles have shown higher delivery efficacy.
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