Biologic drugs such as peptides and proteins are an important class of pharmaceuticals, but typically suffer from sub-optimal pharmacokinetics (PK). The efficient synthesis of polymer conjugates of protein drugs with tunable PK is critical to optimize their in vivo efficacy. To address this problem, we employed atom transfer radical polymerization (ATRP) to directly grow PEG-like or zwitterionic polymers at the N-terminus of a protein. Our results indicate that a protein-zwitterionic polymer conjugate shows a longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar molecular weight (MW). We also found that the structure of the zwitterionic monomer plays a role in controlling the PK of the conjugate. A zwitterionic polymer conjugate with a one carbon spacer between the anion and cation had a ~1.6X longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar MW while a zwitterionic polymer with a mixture of 1 and 2 carbon spacer (ratio of 1 and 2 carbon spacer is 1:2) had a similar in vivo plasma half-life as the PEG-like comb polymer conjugate.

Site-specific protein-PEG-like/zwitterionic polymer conjugates by in situ atom transfer radical polymerization: A comparative study

249th National Meeting (2015)

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