LPR-1-Mediated targeted intranasal delivery of lentinan-loaded polymeric nanocarriers for GBM therapy via modulation of apoptotic signalling

Abstract

Aim To develop and evaluate a lactoferrin (Lf)-functionalized polyethylene glycol (PEG)-grafted chitosan (CS) nanocarriers (NCs) for low-density lipoprotein receptor-related protein-1 (LRP1)-mediated intranasal delivery of lentinan (LNT) to enhance brain targeting and anti-glioblastoma (GBM) efficacy.Materials and Methods Lf-LNT-PEG-CS-NCs were prepared, optimized, and characterized for particle size, entrapment efficiency, coating efficiency, and release behavior. Ex vivo permeation, cellular uptake, cytotoxicity, apoptosis, pharmacokinetic, and biodistribution studies were performed using U87 MG cells and Wistar rats.Results The optimized NCs exhibited a particle size of 205.3 ± 11 nm, entrapment efficiency of 71.52 ± 0.98%, and coating efficiency of 92.42 ± 0.94%, with sustained drug release for 36 h. The permeation increased by 2.86-fold, while cellular uptake reached 78.38 ± 3.76%. Treatment significantly reduced U87 MG cell viability (84.21 ± 2.75% inhibition) and induced apoptosis with 64.55 ± 2.28% G0/G1 arrest, accompanied by reduced COX-2 (55.81 ± 2.91%) and Bcl-2 (59.65 ± 1.95%) expression and increased caspase-3 (73.10 ± 2.91%). Intranasal administration achieved a CSF Cmax of 46.72 ± 3.78 μg/mL and brain accumulation of 42.83 ± 2.59 μg/mL.Conclusion LRP-1-targeted Lf-LNT-PEG-CS-NCs significantly enhanced intranasal brain delivery, cellular uptake, and apoptotic activity of LNT, demonstrating a promising noninvasive platform for targeted GBM therapy.