The Benefits and Challenges of PEGylating Small Molecules

A versatile technology based on repeating units of polyethylene glycol (PEG), known as PEGylation, was first described in the literature in 1977 (1). PEG is a water-soluble, amphiphilic, nontoxic, and nonimmunogenic compound. It is safely cleared from the body and is currently a component of seven approved macromolecular drugs administered parenterally. Although the primary use of PEGylation has been to improve the physicochemical properties of large molecules, it may also be used with small molecules, provided certain challenges are met.

Small molecules have few sites to which PEGs can be attached without compromising their functionality. In addition, small molecules generally are delivered orally, and formulators believed that PEGylation would compromise oral bioavailability. These challenges have heretofore prevented the technology from being tried successfully on small molecules. A large-PEG prodrug approach to small-molecule PEGylation was unsuccessful. The strategy of permanently attaching a small PEG to a small molecule is unteseted and counterintuitive because low molecular weights are generally favored. These challenges in PEGylating small molecules have been overcome, however.