Role of PEGylation in Passive and Active Targeting of Drugs

Passive targeting drug delivery technique, as illustrated in Fig. 1, mostly depends upon the concentration gradient between the intracellular and extracellular space, created due to high concentration of the drug in the tumor area. PEG conjugates takes the advantage of enhanced permeation and retention (EPR) effect executed by the tumors and gets accumulated in the pathophysiological environment of tumor vessels through leaky vasculature and poor lymphatic drainage. However, this effect cannot be studied with low molecular weight drugs that freely extravagate causing systemic toxicity, and this is a size-dependent effect. PEGylation increases the solubility, size, molecular mass and serum stability of the drugs. For all these reasons, PEGylation is considered to be one of the best methods for passive targeting of anticancer therapeutics.

Fig. 1. A schematic illustration of passive targeting with acid-sensitive PEG-prodrugs that cleave in the extracellular space.

The concept of active targeting of drugs is based on the idea of conjugating drug molecules to targeting entities (antibodies, ligands, etc.) for specific interaction with the structures present on the cell surface for targeted delivery of the anticancer agent. The fate of the pro-drug is dictated by the targeting molecule and the linker molecule present on the pro-drug. The targeting moiety essentially decides the type of cancer cell for the act of therapeutics. Further, depending on the linker molecule, the drug gets entry into the tumor cell by either of the two ways: (i) receptor-mediated internalization of the whole pro-drug by endocytosis and subsequent degradation by endosomal/lysosomal pathway (2), or (ii) receptor-independent internalization of the drug into targeted cells after extracellular cleavage of the pro-drug (Fig. 3) . PEGylated pro-drugs can be efficiently conjugated to targeting moieties by different conjugation chemistry in order to achieve the goal of active targeting. The targeted delivery of the PEGylated drugs at the desired site causes high bioavailability and low systemic toxicity.

Fig. 2. A schematic illustration of receptor mediated internalization and endosomal/lysosomal degradation of the pro-drug during active targeting.

Fig. 3. A schematic illustration of Active Targeting with acid sensitive PEG- prodrugs which cleaves in the extracellular space.