The Encapsulation of Citicoline within Solid Lipid Nanoparticles Enhances Its Capability to Counteract the 6‐Hydroxydopamine‐Induced Cytotoxicity in Human Neuroblastoma SH‐SY5Y Cells

: (1) Backgrond: Considering the positive effects of citicoline (CIT) in the management of some neurodegenerative diseases, the aim of this work was to develop CIT‐Loaded Solid Lipid Nanoparticles (CIT‐SLNs) for enhancing the therapeutic use of CIT in parkinsonian syndrome; (2) Methods: CIT‐SLNs were prepared by the melt homogenization method using the self‐emulsifying lipid Gelucire® 50/13 as lipid matrix. Solid‐state features on CIT‐SLNs were obtained with FT‐IR, thermal analysis (DSC) and X‐ray powder diffraction (XRPD) studies. (3) Results: CIT‐SLNs showed a mean diameter of 201 nm, −2.20 mV as zeta potential and a high percentage of entrapped CIT. DSC and XRPD analyses evidenced a greater amorphous state of CIT in CIT‐SLNs. On confocal microscopy, fluorescent SLNs replacing unlabeled CIT‐SLNs released the dye selectively in the cytoplasm. Biological evaluation showed that pre‐treatment of SH‐SY5Y dopaminergic cells with CIT‐SLNs (50 μM) before the addition of 40 μM 6‐hydroxydopamine (6‐OHDA) to mimic Parkinson’s disease’s degenerative pathways counteracts the cytotoxic effects induced by the neurotoxin, increasing cell viability with the consistent maintenance of both nuclear and cell morphology. In contrast, pre‐treatment with CIT 50 and 60 μM or plain SLNs for 2 h followed by 6‐ OHDA (40 μM) did not significantly influence cell viability. (4) Conclusions: These data suggest an enhanced protection exerted by CIT‐SLNs with respect to free CIT and prompt further investigation of possible molecular mechanisms that underlie this difference.