Encapsulation and controlled release of the therapeutic neuropeptides somatostatin and oxytocin from the lipidic bicontinuous cubic phase

Therapeutic delivery of neuropeptides including oxytocin and somatostatin is associated with numerous difficulties including low stability, low oral bioavailability and a short half-life in vivo. For delivery to the brain, these issues are exacerbated by difficulties in crossing the blood-brain barrier. Lipid-based nanomaterials may offer specific advantages for the delivery of therapeutic peptides including good biocompatibility, retention of peptide activity, and controlled release properties. Herein we have investigated the use of the lipid bicontinuous cubic phase as a depot formulation for the controlled release of the neuropeptides oxytocin and somatostatin. Retention of the cubic architecture was confirmed up to high peptide concentrations of at least 30 mg/mL for both peptides. Encapsulation had only minimal effect on the peptide secondary structure in both cases. Controlled release of the peptides from the cubic phase was diffusion controlled over the first 24 hours. The time-dependent self-assembly of somatostatin into nanofibrils within the bicontinuous cubic phase led to a unique two-stage release mechanism, with diffusion-controlled release of the peptide monomer over the first 24 hours followed by a much slower linear release of the peptide from the nanofibrils. Results suggest that the lipid bicontinuous cubic phase is a highly prospective nanomaterial for the encapsulation and controlled release of neuropeptide therapeutics.