Quantitative Blood–Brain Barrier Transport, Brain Microdialysis and Pharmacokinetic–Pharmacodynamic Modeling of Taxifolin-Functionalized Rivastigmine Liposomes in Alzheimer’s Models

Abstract

Background: Alzheimer’s disease (AD) is associated with cholinergic dysfunction and oxidative stress.
Rivastigmine has limited blood–brain barrier (BBB) penetration and rapid clearance, while taxifolin possesses
antioxidant and neuroprotective properties but suffers from poor bioavailability. Aim: The aim of the study is
to develop taxifolin-functionalized rivastigmine liposomes (Tax-Riva-Lipo) for enhanced BBB transport, brain
targeting, and pharmacokinetic–pharmacodynamic (PK/PD) optimization. Materials and Methods: Tax-Riva-
Lipo was prepared by thin-film hydration and characterized for particle size, zeta potential, and encapsulation
efficiency. BBB transport was evaluated using the hCMEC/D3 Transwell model. In vivo pharmacokinetics,
biodistribution, and brain microdialysis were performed in rodents. Pharmacodynamic effects were assessed
using behavioral studies, cholinesterase activity, oxidative stress markers, and PK/PD modeling. Results: Tax-
Riva-Lipo showed nanosized vesicles (100–130 nm) with efficient encapsulation and functionalization. The
formulation significantly enhanced BBB permeability via caveolae-mediated transport and improved plasma
exposure, half-life, and brain retention. Enhanced cognitive performance, stronger acetylcholinesterase inhibition,
reduced oxidative stress (↓malondialdehyde, ↑superoxide dismutase, ↑glutathione), and improved targeting
indices were observed. PK/PD modeling demonstrated greater potency (lower IC₅₀) and efficacy (higher Emax).
Conclusion: Tax-Riva-Lipo improved brain delivery and therapeutic efficacy through combined cholinergic and
antioxidant mechanisms, highlighting its potential as a promising strategy for AD treatment.