Stimuli-Responsive Sulfoxide Polymer–Protein Conjugates with Improved Pharmacokinetics and Tumor Delivery

A growing number of reports of poly(ethylene glycol) (PEG)-associated immunogenicity have prompted the development of alternative polymers for bioconjugation to assist in overcoming the poor in vivo pharmacokinetic profile of proteins. In this study, we demonstrate the development of transferrin (Tf) protein–polymer conjugates using a highly hydrophilic sulfoxide polymer (poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA)) that has recently emerged as a promising class of low-fouling polymer. A cleavable thioketal linker between the protein and polymer enabled successful protein release when the conjugates were exposed to an environment rich in reactive oxygen species. Cleavage of the polymer circumvents the loss of protein activity upon chemical modification. The Tf-PMSEA conjugate was capable of significantly improving the in vivo pharmacokinetics of the protein and consequently enabled higher tumor accumulation of Tf-PMSEA in tumor-bearing mice compared to the PEGylated counterpart. This demonstrated the potential of PMSEA to be utilized in therapeutic delivery applications as a promising alternative to PEG.