PEGylation was usually recognized as a gold standard to improve the stability and half-life of protein drugs. Although hugely succussed, the drawbacks of PEGylated proteins, such as accumulated toxicity and anti-PEG antibodies, compromise the full therapeutic potential of protein drugs. With super-hydrophilicity and superior anti-fouling properties, zwitterionic polymer is gradually accepted as an alternative to PEG for protein conjugation. In this review, we discuss a series of features exhibited by protein-zwitterionic polymer conjugate that outperform PEGylated protein.

Abstract

To render protein drugs more suitable for clinical treatment, PEGylation has been widely used to ameliorate their inherent deficiencies, such as poor stability, rapid elimination in the bloodstream, and high immunogenicity. While increasingly PEGylated protein drugs have been approved by the FDA, the non-degradability of PEG and the emergence of anti-PEG antibodies after injection raise concerns about their cumulative chronic toxicity and long-term therapeutic efficacy. Zwitterionic polymer, with a unique structure containing equal amounts of positively charged and negatively charged groups, shows a different hydration behavior to PEG, which may be a superior PEG alternative for protein conjugation. In this concept review, a series of features beyond that of PEGylated protein exhibited by protein-zwitterionic polymer conjugate are discussed and some suggestions are presented for their future direction.