PEGylated Polymer–Lipid Hybrid Nanoparticles to Enhance In Vivo Exposure and Uptake of Repaglinide in Brain Cells to Treat Diabetes-Linked Neurodegenerative Disorders

Repaglinide (REP), an antidiabetic drug, is recently explored in ameliorating neurodegenerative disorders (Huntington’s and Alzheimer’s disease) by targeting neuronal calcium sensors (DREAM/ATF6 pathway). The repurposing of REP faces odds due to its short half-life and poor brain permeability. To circumvent these, we have developed and evaluated PEGylated nanocarriers, i.e ., polymer–lipid hybrid nanoparticles (PLHNPs), for oral delivery of REP in the treatment of diabetes mellitus (DM)-linked neurodegenerative disorders. PLHNPs were prepared using a hybrid polymer–lipid (DSPE-PEG 2000 ), phospholipids (SPC), and a biodegradable polymer, PLGA. The evaluation of the formulation suggests that PEGylated nanocarriers (PLHNPs) had a spherical shape with a particle size of 125.09 ± 3.21 nm and a polydispersity index of 0.18 ± 0.05 and exhibited significant improvement in cell viability and uptake (21%) in neuroblastoma cells (SHSY-5Y). Also, PLHNPs enhanced intestinal absorption (3.3-fold) and brain permeation by in situ studies. Moreover, pharmacokinetic studies suggest that administration of PLHNPs in wistar rats improved the pharmacokinetic parameters such as t max (4.4-fold), C max (1.9-fold), and area under the curve (4.3-fold) compared to REP. Further, efficacy studies in a DM-induced neurodegenerative murine model showed a significant ( p < 0.0001) improvement in the biochemical and behavioral parameters after the oral administration of PLHNPs compared to REP. Hence, it could be concluded that oral administration of PEGylated nanocarriers promoted the brain delivery of REP, and PLHNPs were more efficacious due to their core–shell nanoparticulate structure formed by the DSPE-PEG hybrid lipid–polymer, imparting gastrointestinal stability, enhanced permeation, and reduced immunogenicity.