Striving for Uniformity: A Review on Advances and Challenges To Achieve Uniform Polyethylene Glycol

Poly(ethylene glycol) (PEG) is the polymer of choice in drug delivery systems due to its biocompatibility and hydrophilicity. For over 20 years, this polymer has been widely used in the drug delivery of small drugs, proteins, oligonucleotides, and liposomes, improving the stability and pharmacokinetics of many drugs. However, despite the extensive clinical experience with PEG, concerns have emerged related to its use. These include hypersensitivity, purity, and nonbiodegradability. Moreover, conventional PEG is a mixture of polymers that can complicate drug synthesis and purification leading to unwanted immunogenic reactions. Studies have shown that uniform PEGylated drugs may be more effective than conventional PEGylated drugs as they can overcome issues related to molecular heterogeneity and immunogenicity. This has led to significant research efforts to develop synthetic procedures to produce uniform PEGs (monodisperse PEGs). As a result, iterative step-by-step controlled synthesis methods have been created over time and have shown promising results. Nonetheless, these procedures have presented numerous challenges due to their iterative nature and the requirement for multiple purification steps, resulting in increased costs and time consumption. Despite these challenges, the synthetic procedures went through several improvements. This review summarizes and discusses recent advances in the synthesis of uniform PEGs and its derivatives with a focus on overall yields, scalability, and purity of the polymers. Additionally, the available characterization methods for assessing polymer monodispersity are discussed as well as uniform PEG applications, side effects, and possible alternative polymers that can overcome the drawbacks.