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

Abstract

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 DMinduced 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.

Small Scale, Big Impact: Nanotechnology-Enhanced Drug Delivery for Brain Diseases

“…This study demonstrated that this hybrid nanoparticle increased the targeting ability of Riv to the brain, but therapeutic efficacy should be investigated in future studies. Wadhwa et al administered pegylated polymer–lipid hybrid nanoparticles via oral delivery to treat diabetes-linked neurodegenerative diseases, and results showed that the mice treated with nanoparticles had improved retention memory . This study provided a comprehensive investigation in vitro and in vivo , including drug design, drug release, therapeutic efficacy, and biodistribution analysis, which indicated a promising strategy to enhance drug delivery for diabetes-linked neurodegenerative diseases.…”

PEG–Lipid–PLGA Hybrid Particles for Targeted Delivery of Anti-Inflammatory Drugs

“…The lipid layer can consist of lecithin or cholesterol and an additional lipid, e.g., DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) or DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanol-amine), which are conjugated with polyethylene glycol (PEG). The function of the lipid layer is to ensure biocompatibility and stability, while the functional PEGylated lipids additionally improve the water solubility of the particles, reducing the aggregation tendency through steric stabilization [ 11 , 13 , 15 ]. The PEG shell serves as a stealth coating that prevents opsonization, resulting in a prolonged circulation time of DDS in the bloodstream [ 16 , 17 ].…”