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

Abstract

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 , 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 18-SS-EM1 and C 18-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 18-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 18-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C 18-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C 18-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C 18-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.

Engineering small molecule nanodrugs to overcome barriers for cancer therapy

“…(B) In vitro cytotoxicity of CPT, OEG-DiCPT, DOX⋅HCl, and OEG-DiCPT/DOX⋅HCl to MCF-7 breast cancer cells determined by MTT assay. 73 Copyright 2010, American Chemical Society stearic acid, 78 lauric acid, 79 phospholipid, [39][40][41][42][43] and so forth have been reported for self-assembled drug delivery. For example, Shen et al 73 reported the concept of directly using ethylene oxide oligomer to construct nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release.…”

Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly

“…Alkyl chain modification of peptides has received much attention in recent years (Evans et al 2020 ; Liu et al 2019 ; Yang et al 2023 ), since alkyl chain introduction renders peptides hydrophobic, which can induce peptide self-assembly and lead to the improvement of peptide drug stability (Gao et al 2023 ; Ding et al 2023 ; Yang et al 2023 ). Our previous study showed that self-assembled micelles formed by N-terminal myristoylated MVIIA at high concentrations can prolong the duration of analgesic effect, improve serum stability, and significantly reduce or even eliminate side effects (Ding et al 2023 ).…”