The Benefits and Challenges of PEGylating Small Molecules

Polyethylene glycol (PEG) conjugation is a highly effective technical and commercial strategy to develop macromolecules. The authors explain the benefits and process of PEGylation and how it may be applied to small molecules.
Jul 02, 2008

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.

PEGs can be designed with various pharmacokinetic-altering architectures. They can be synthesized as linear, branched, or forked structures with functional groups at one or more termini to enable several conjugation strategies. Linkers covalently attach the molecule to the parent drug directly or indirectly. The choice of linkers enables PEG to be placed in various positions on the molecule. Placement can fine tune a drug's pharmacokinetic properties and maintain its efficacy. Overall, PEGylated molecules demonstrate enhanced solubility and stability, on the shelf and in vivo, and an improved safety profile.

Table I: Potential benefits of PEG technology.
Conjugation bonds can be stable or releasable to create entirely new compounds or novel prodrugs. Stable PEG linkages create new pharmaceutical entities with respect to such pharmacokinetic parameters as circulating half life, clearance, absorption, and bioavailability. PEGs may harm the pharmacodynamic properties of target binding because of steric hindrance. The releasable attachments used in PEG prodrugs enable controlled drug release through the choice of architecture, attachment sites, and linker molecules.

Table II: PEGylated macromolecular drugs.
PEGylation imparts valuable, and in some cases crucial, pharmacokinetic properties to macromolecules, whether stable molecules or prodrugs, and has emerged as the dominant strategy for improving macromolecular drugs. PEGylation is associated with numerous clinical benefits in these drugs, including increased efficacy, decreased side effects, and lower frequency of dosing (see Table I). Table II shows the current, macromolecular PEG landscape. The technology is applicable to many therapeutic areas (e.g., oncology, metabolic diseases, and infectious diseases) and to various macromolecular classes (e.g., cytokines, antibodies, enzymes, and aptamers).