New insights into the activity of Anle138b from in vitro models of Parkinson’s disease.

Parkinson’s disease (PD) is a common neurodegenerative disorder marked by dopaminergic neuron loss and dopamine deficiency. While Levodopa remains the primary treatment, its long-term use leads to motor complications and fails to halt disease progression. Recent research focuses on alpha-synuclein (α-syn) aggregation, a key pathological mechanism. Anle 138b, a promising small molecule inhibitor of α-syn and prion protein oligomerization, can cross the blood-brain barrier (BBB), but its poor water solubility limits formulation, reducing bioavailability. Intranasal administration is a promising alternative, bypassing the BBB via the olfactory mucosa for faster brain access and fewer systemic effects. This study investigates solid lipid nanoparticles (SLNs) as a water-soluble delivery system for Anle 138b. Cytocompatibility was evaluated on RPMI 2650 (nasal), SH-SY5Y (neuronal), and differentiated SH-SY5Y (Parkinsonian) cells. We also tested SLN-Anle 138b combined with commercial nutraceuticals on differentiated SH-SY5Y cells to assess its commercial feasibility. In all cellular models, Anle 138b SLNs showed good tolerability at 1–10 µM for 24 h. Moreover, the combination with commercial nutraceuticals did not alter cell viability, as resulted from differentiated SH-SY5Y cell studies. In conclusion, our data demonstrate the cytocompatibility of Anle 138b-loaded SLNs and support their use as a potential nose-to-brain delivery system for PD treatment.