Sitagliptin-Loaded Lipid Nanoparticles: Shuttles for Alzheimer’s Disease Treatment

Neuroinflammation plays a key role in the progression of various neurodegenerative diseases, including Alzheimer’s disease (AD). Sitagliptin, a widely used antidiabetic drug, has shown neuroprotective and anti-inflammatory effects, including the reduction of tumor necrosis factor-α (TNF-α) expression. This study aimed to design, develop, and evaluate lipid-based nanoparticle formulations of sitagliptin for enhanced brain delivery and treatment of neuroinflammation. Sitagliptin-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were prepared using homogenization and ultrasonication, with formulation parameters optimized through experimental design. The optimized nanoparticles were characterized for physicochemical properties, drug release behavior, cytotoxicity, and in vivo efficacy. Both formulations successfully encapsulated sitagliptin and exhibited mean particle sizes of approximately 50 nm. Drug release studies demonstrated a slower release profile for SLNs compared with NLCs. Cytotoxicity assessment using HepG2 cells indicated that both formulations were safe at low concentrations, while NLCs showed a more favorable safety profile at higher concentrations. In a mouse model of neuroinflammation, both nanoparticle systems improved behavioral outcomes and significantly reduced TNF-α expression in brain tissue, indicating enhanced brain delivery and anti-inflammatory activity. Overall, both SLNs and NLCs effectively attenuated neuroinflammation; however, NLCs demonstrated superior efficacy and safety, highlighting their potential as a promising delivery platform for sitagliptin in the treatment of AD-associated neuroinflammation.