TY - JOUR
T1 - Optimizing Angiopep-2 Density on Polymeric Nanoparticles for Enhanced Blood–Brain Barrier Penetration and Glioblastoma Targeting
T2 - Insights From In Vitro and In Vivo Experiments
AU - Zhang, Weisen
AU - Refaat, Ahmed
AU - Li, Haoqin
AU - Zhu, Douer
AU - Tong, Ziqiu
AU - Nicolazzo, Joseph Anthony
AU - Peng, Bo
AU - Bai, Hua
AU - Esser, Lars
AU - Voelcker, Nicolas Hans
N1 - Publisher Copyright:
© 2025 The Author(s). Advanced Functional Materials published by Wiley-VCH GmbH.
PY - 2025
Y1 - 2025
N2 - The blood–brain barrier (BBB) poses a formidable challenge to drug delivery to the brain. One promising approach involves receptor-mediated transcytosis via Angiopep-2 peptide (Ang-2)-conjugated nanoparticles. However, the influence of Ang-2 density on BBB penetration remains poorly understood. We developed a versatile polymeric nanoparticle system with tunable Ang-2 surface density and systematically examined its influence on BBB penetration through various in vitro assays and an in vivo study. The results reveal a nuanced relationship between ligand density and BBB penetration across experimental setups. In 2D cell culture, Ang-2 density positively correlates with nanoparticle association in human cerebral microvascular endothelial cells (hCMEC/D3) with a distinctive inflection point. Conversely, in the Transwell model, higher Ang-2 density negatively correlate with BBB penetration, while the BBB-glioblastoma (GBM)-on-a-chip shows the opposite trend. Disparities may be due to differences in avidity under static versus dynamic conditions, modulating nanoparticle interactions due to fluidic forces. In vivo studies align with the microfluidic model. Loading doxorubicin into the optimized nanoparticles achieves controlled pH-responsive release and enhanced anticancer effects against U87 GBM cells in 2D cell cultures and a 3D BBB-GBM-on-a-chip. These results underscore the importance of optimizing Ang-2 density for BBB penetration and emphasize the utility of dynamic models for the preclinical assessment of brain-targeting nanoparticles.
AB - The blood–brain barrier (BBB) poses a formidable challenge to drug delivery to the brain. One promising approach involves receptor-mediated transcytosis via Angiopep-2 peptide (Ang-2)-conjugated nanoparticles. However, the influence of Ang-2 density on BBB penetration remains poorly understood. We developed a versatile polymeric nanoparticle system with tunable Ang-2 surface density and systematically examined its influence on BBB penetration through various in vitro assays and an in vivo study. The results reveal a nuanced relationship between ligand density and BBB penetration across experimental setups. In 2D cell culture, Ang-2 density positively correlates with nanoparticle association in human cerebral microvascular endothelial cells (hCMEC/D3) with a distinctive inflection point. Conversely, in the Transwell model, higher Ang-2 density negatively correlate with BBB penetration, while the BBB-glioblastoma (GBM)-on-a-chip shows the opposite trend. Disparities may be due to differences in avidity under static versus dynamic conditions, modulating nanoparticle interactions due to fluidic forces. In vivo studies align with the microfluidic model. Loading doxorubicin into the optimized nanoparticles achieves controlled pH-responsive release and enhanced anticancer effects against U87 GBM cells in 2D cell cultures and a 3D BBB-GBM-on-a-chip. These results underscore the importance of optimizing Ang-2 density for BBB penetration and emphasize the utility of dynamic models for the preclinical assessment of brain-targeting nanoparticles.
KW - angiopep-2
KW - blood–brain barrier
KW - microfluidic organ-on-a-chip model
KW - polymeric nanoparticles
KW - surface density
UR - http://www.scopus.com/inward/record.url?scp=105003816725&partnerID=8YFLogxK
U2 - 10.1002/adfm.202425165
DO - 10.1002/adfm.202425165
M3 - 文章
AN - SCOPUS:105003816725
SN - 1616-301X
JO - Advanced Functional Materials
JF - Advanced Functional Materials
ER -