The clinical applications of etanercept (Enbrel), an emerging therapeutic protein for rheumatoid arthritis (RA), are limited by its instability and low bioavailability. In this study, a long-term and efficient therapeutic nanocomplex formulation for RA treatment was developed in the form of a temperature-modulated noncovalent interaction controllable (TMN) complex based on a temperature-sensitive amphiphilic polyelectrolyte (succinylated pullulan-g-oligo(L-lactide); SPL). The TMN complexes were prepared by simply mixing the negatively charged SPL copolymer and the positively charged etanercept via electrostatic interaction at 4 °C below the polymer's clouding temperature (CT), and the resulting complex demonstrated significantly improved salt and serum stability with increased hydrophobic interactions at temperatures (physiological condition, 37.5 °C) above the CT. An in vitro study of the bioactivity of etanercept indicated that the TMN complex improves the long-term stability of etanercept in an aqueous environment because of the exposure of the functional active site and the molecular chaperone-like effect of the hydrophobic copolymer. This formulation possessed prolonged in vivo pharmacokinetic parameters. In a collagen-induced arthritis RA rat model, we verified the outstanding therapeutic effect of the TMN complexes. These results imply that this approach would be widely applied to protein and peptide delivery systems.
Keywords: Drug delivery; Electrostatic interactions; Etanercept; Noncovalent interactions; Rheumatoid arthritis.
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