Novel zwitterionic densely charged neutral sulfobetaine polymeric micelles for oral delivery of therapeutic peptides: a proof-of-concept study

Densely charged but neutral sulfobetaine polymeric micelles (PMs) were designed with the aim of efficiently permeating the intestinal mucus and releasing the intact peptide cargo close to the intestinal epithelial surface. Using RAFT chemistry, butyl methacrylate and dimethyl aminoethyl methacrylate copolymers were synthesised and then reacted with propane sultone to form amphiphilic block copolymers comprising hydrophilic zwitterionic sulfobetaine and lipophilic butyl methacrylate (BMA). Small (diameter <50 nm), spherical BMA-sulfobetaine PMs with a near neutral surface charge potential and loaded with a model peptide cargo, the GLP1-agonist peptide exenatide, were then formed by nanoprecipitation. In vitro peptide release studies from the PMs showed that less than 0.9% of the peptide load was released within the first 2 h (i.e. there was no ‘burst’ effect), with the release unaffected by highly acidic conditions. Thereafter, a sustained release was evident with 43% of the peptide load released in 24 h. In vitro screening (cytotoxicity assay) showed that the PMs did not cause loss of epithelial cell viability. Multiple particle tracking showed that the PMs were very highly permeant through the intestinal mucus. An in vivo non-clinical rodent pharmacokinetic study demonstrated the oral delivery of the exenatide-loaded PMs to achieve an extent of peptide bioavailability of 13% relative to subcutaneous (s.c.) exenatide solution injection. A pharmacodynamic study showed the efficacy of the oral exenatide-loaded PMs with significant reductions in blood glucose following a glucose challenge test. In conclusion, a novel family of sulfobetaine PMs have been demonstrated as stable carriers, efficiently permeating the intestinal mucus and with the potential for exploitation in the oral delivery of therapeutic peptides.