Leu-Enkephalin Lipid Prodrug Nanoparticles: Relationship between Nanoparticles’ Structure, Interaction with Bovine Serum Albumin, and Analgesic Activity

Recently, we proposed in a paper a novel nanomedicine approach based on a versatile bioconjugation linkage (amide, diglycolate, or acylal) between the Leu-enkephalin (LENK), an endogenous neuropeptide, and the squalene (SQ), a natural and biocompatible lipid. The nanoformulation of the resulting bioconjugates allowed the specific delivery of LENK into inflamed tissues for efficient pain control after their intravenous administration. However, the variability of the analgesic profiles exhibited by the three types of LENK-SQ nanoparticles (NPs) remains not well understood. This study investigates the influence of the LENK-SQ NP composition on their supramolecular organization and their interaction with blood proteins. To achieve this objective, a physicochemical study was carried out using complementary techniques such as dynamic light scattering (DLS), small/wide-angle X-ray and neutron scattering (SAXS-WAXS and SANS), and circular dichroism (CD). This study brought together some important information, allowing us to shed light on the crucial link between nanoparticles' structure, stability, and analgesic activity.