Targeted Delivery of Quercetin to the Brain via a Modified Polymeric Nanocarrier

Quercetin (Qt) exhibits significant neuroprotective potential in Alzheimer's disease; however, its clinical translation is limited by poor solubility, low permeability, and inadequate brain bioavailability. In this study, a modified polymeric nanocarrier was developed to enhance Qt delivery to the brain. Polyethyleneimine (PEI) was conjugated with polyethylene glycol (PEG) and further functionalized with phenylalanine to reduce PEI-associated toxicity and improve brain-targeting efficiency. Successful polymer synthesis was confirmed by FT-IR spectroscopy, showing characteristic S─S bond formation at 790 cm^{- 1}, mass spectrometry (m/z 1087.3), and differential scanning calorimetry. Nanoparticles were optimized using a Quality by Design approach, yielding an experimental particle size of 161.4 ± 1.10 nm, zeta potential of 15.9 ± 2.5 mV, and high entrapment efficiencies of 84.21 % and 86.74 % for Qt-PEI-Np and Qt-PEI-PEG-S-S-AA-Np, respectively. SEM analysis revealed spherical nanoparticles with nanoscale surface roughness and good stability. In vitro release studies demonstrated sustained Qt release (98 % over 48 h). MTT assays and cytokine analysis (TNF-α, IL-1β, IL-6) confirmed biocompatibility. Enhanced intestinal permeability, absence of hippocampal toxicity, and effective BBB transport further support the potential of this nanocarrier for targeted neurotherapeutic delivery.