PEGylation, the ultimate strategy to improve the in vivo efficiency of bioactive compounds

PEGylation is a chemical reaction that allows the conjugation of a polyethylene-glycol (PEG) group to another compound. In the industry, since the commercial release of Adagen, the first approved PEGylated drug, PEGylation has proven to be a successful strategy for the generation of efficient drugs. This technique has been widely applied because it contributes to the prolongation of the half-life of the compound in vivo. PEGylation provides better pharmacokinetics, improved stability, enhanced solubility, increased resistance to proteolytic degradation, and reduced immunogenicity, toxicity and plasma clearance. This technique is especially suited to the in vivo use of small active peptides, which have an extremely short half-life in vivo usually ranging from 4 minutes up to 15 minutes. Indeed, another important benefit of PEGylation is the resultant increase in molecular weight, which prevents fast renal clearance occurring when peptides displays a molecular weight smaller than 8,000. Thus, PEGylation really boosts the in vivo activity of the PEGylated molecule. On the other hand, PEGylation has a few drawbacks. The addition of the PEG moiety may alter the conformation of the original molecule leading to partial or complete loss of activity. Moreover, it may affect the binding of the original molecule to its target on the cell and modify tissue distribution. In addition, due to chemistry limitations, the PEGylated compound can be heterogeneous because of variations both in the exact size of the PEG polymer, and in the number and location of conjugated PEGs. Since PEGylated drugs have been used for more than 20 years, side effects of PEGylation have been reported showing, however, no important toxicity. PEGs can accumulate in various organs including the liver. In cells, such as macrophages, PEGs causes vacuolation in the cytoplasm. However, the types of cells that are affected and pattern of distribution not only rely on PEG size but also on the PEG-conjugated molecule. Yet, modern techniques of PEGylation using site-directed PEGylation, mono- or multi-branched PEG have the potential to reduce these drawbacks. Furthermore, the possibility to conjugate new functional group such as fluorescent PEG or lipid PEG gives rise to an interesting number of additional applications.