Intranasal administration of silibinin-loaded pullulan acetate nanocarriers: A pH-responsive approach for brain targeting in Alzheimer's disease

Abstract

Despite recent advancements, the need for effective Alzheimer's Disease Therapy (ADT) still exists due to the complexities of delivering and maintaining the therapeutic concentrations of promising active agents in the brain. Silibinin, a natural agent, has shown to inhibit Aβ aggregation and reduce cognitive dysfunction in Alzheimer's Disease (AD) models. The present research aimed to synthesize pH-sensitive pullulan acetate (PA) via three synthetic processes and fabricate intranasally-administer silibinin-loaded PA nanoparticles (SPNs) for brain-specific ADT. SPNs were optimized by varying polyvinyl alcohol (PVA) and PA concentrations. Optimized SPNs exhibited a particle size (PS) of 293.50 ± 6.49 nm, zeta potential (ZP) of −5.82 ± 0.73 mV and % entrapment efficiency (% EE) of 88.74 %. Attenuated total reflection - Fourier Transform Infrared Spectroscopy (ATR-FTIR) and Differential Scanning Calorimetry (DSC) studies confirmed silibinin-PA interactions, the amorphous nature of SPNs and entrapment of silibinin in SPNs. Scanning Electron Microscopy (SEM) displayed the size and spherical morphology of SPNs. Cumulative release of 34.61 ± 0.52 % in pH 6.0 and 90.96 ± 0.53 % in pH 7.2 over 24 h demonstrated the pH-sensitive sustained release profile of SPNs. Ex-vivo studies using nasal goat mucosa showed 85.84 ± 1.15 % drug permeation in 24 h. Brain-uptake study performed on Albino Wistar rats revealed a sustained release profile of SPNs with an AUC0-12 of 1284.70 ng/ml*h, Cmax of 159 μg/mL and tmax of 12 h. Overall, SPNs are promising carriers for the brain-targeted delivery of silibinin for effective ADT.