Abstract
Polyelectrolyte complexes permit the tunable, aqueous complexation of therapeutic peptides; however, their reliance on electrostatic and hydrophobic interactions limits complexation with weakly charged, hydrophilic peptides. While the peptide charge and hydrophobicity can be modified to encourage complexation, permanent modifications can hinder peptide activity and eventual release. Here, we show that esterifying the therapeutic peptide α-carboxyl terminus 11 (αCT11) reversibly increases its net charge and hydrophobicity, enabling complexation with anionic poly(methacrylic acid) and subsequent dissociation, as esters hydrolyze over 24 h. Prior to hydrolysis, hydrophobic aspartimide intermediates appear to promote aggregation, prolonging complexation. Further emphasizing the importance of hydrophobicity, replacing the aromatic polymer chain end with a less hydrophobic group abrogated complexation. Together, these studies showcase how esterification can be leveraged for reversible polymeric complexation of weakly charged, hydrophilic peptides and present exciting prospects for using polymer hydrophobicity to tune reversible complexation to meet patient and delivery method-specific needs.