Lactoferrin- and antitransferrin-modified liposomes for brain targeting of the NK3 receptor agonist senktide: Preparation and in vivo evaluation

The aim of this work was to evaluate the capability of lactoferrin- and antitransferrin-modified long circulating liposomes to deliver the hydrophilic peptide senktide, a selective NK3 receptor agonist unable to cross the blood brain barrier, to central nervous system by using an indirect method based on in vivo microdialysis studies to estimate the responsiveness of nucleus accumbens shell dopamine to senktide. To this purpose, senktide was encapsulated in different targeted and not-targeted stealth liposomes prepared using film hydration method. Formulations were characterized in terms of morphology, size distribution, zeta potential, encapsulation efficiency, and antibody presence on the liposome surface. In vivo microdialysis studies were performed injecting intravenously the senktide-loaded liposomes and comparing obtained dopamine levels with those found with the free senktide given intracerebroventricularly. Results showed that all vesicles were spherical, small in size (around 120 nm), homogeneously dispersed, and slightly negatively charged. TEM analysis, using an anti IgG secondary antibody with 10 nm gold nanoparticles at its distal end, demonstrated the successful linkage of the antibody on the liposomal surface.Intravenously administered in rats, senktide-loaded targeted stealth liposomes elicited a significant increase of dialysate dopamine in the nucleus accumbens shell, which was comparable to that of the free senktide given intracerebroventricularly when antitransferrin-targeted liposomes were tested. On the contrary, control stealth liposomes did not affect dopamine levels. Senktide brain levels were higher using the antitransferrin-targeted liposomes in comparison with the lactoferrin ones, while the opposite was obtained in the liver tissue where the highest senktide accumulation was always found.

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