Targeting the blood-brain barrier with lipoprotein-mimicking nanoparticles loaded with flurbiprofenaxetil and coated with apolipoprotein E

Laabs, M.; Mulac, D.; Langer, K.

Abstract

In previous studies, it has been demonstrated that lipoprotein-mimicking nanoparticles with a solid lipid core of cholesteryl oleate, a lecithin coating and adsorptively bound apolipoprotein E3 (ApoE) may serve as a potential vehicle for drug delivery to the central nervous system. In this study, the impact of drug characteristics, particularly lipophilicity, was evaluated to achieve a stable incorporation of model drugs into these lipid-based nanoparticles (LNPs). This study explored the lipophilicity of flurbiprofen, a potential drug in the treatment of Alzheimer's disease (AD), and its prodrug flurbiprofenaxetil across varying pH levels. Our findings highlight how flurbiprofen's lipophilicity was influenced by its protonation state, affecting its incorporation into LNPs and consequently its release behaviour under physiological conditions, while flurbiprofenaxetil showed minimal variations due to its chemical structure. We also investigated the interaction between lipoprotein mimicking nanoparticles and primary porcine brain capillary endothelial cells to improve drug delivery across the blood-brain barrier (BBB). Permeation studies indicated that modification with ApoE enhanced the bidirectional permeability of LNPs across the BBB through receptor-mediated transcytosis. Furthermore, we demonstrated and identified the uptake mechanism involving the low density lipoprotein receptor-related protein 1 (LRP1), allowing these LNPs to be recognized by the same receptors as endogenous lipoproteins. Overall, these findings highlight the potential of ApoE modified LNPs as a promising strategy for targeted drug delivery to the brain.