Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery.

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH, EM-1), an endogenous μ-opioid receptor ligand with strong antinociceptive activity, is not in clinical use because of its limited metabolic stability and membrane permeability. In this study, we develop a short-peptide self-delivery system for brain targets with the capability to deliver EM-1 without vehicle. Two amphiphilic EM-1 derivatives, C-SS-EM1 and C-CONH-EM1, were synthesized by attaching a stearyl moiety to EM-1 via a disulfide and amide bond, respectively. The amphiphilicity of EM-1 derivatives enabled self-assembling into nanoparticles for brain delivery. The study assessed morphology, circular dichroism, and metabolic stability of the formulations, as well as their pharmacodynamics and in vivo distribution, directly monitored by near-IR fluorescence imaging in mouse brains. In aqueous solution, the C-SS-EM1 derivative self-assembled into spherical nanostructures with a diameter of 10-20 nm. Near-IR fluorescence analysis visualized the accumulation of the peptides in the brain. Importantly, the analgesic effect of C-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C-SS-EM1 nanoparticles, which integrate the advantages of lipidization, nanoscale characteristics and, labile disulfide bonds, represent a promising strategy for brain delivery of short peptides.