10.6084/m9.figshare.5640157.v1
Lijuan Wen
Lijuan
Wen
Yanan Tan
Yanan
Tan
Suhuan Dai
Suhuan
Dai
Yun Zhu
Yun
Zhu
Tingting Meng
Tingting
Meng
Xiqin Yang
Xiqin
Yang
Yupeng Liu
Yupeng
Liu
Xuan Liu
Xuan
Liu
Hong Yuan
Hong
Yuan
Fuqiang Hu
Fuqiang
Hu
VEGF-mediated tight junctions pathological fenestration enhances doxorubicin-loaded glycolipid-like nanoparticles traversing BBB for glioblastoma-targeting therapy
Taylor & Francis Group
2017
VEGF
glioblastoma
pathological
tight junctions
fenestration
2017-11-28 10:56:52
Journal contribution
https://tandf.figshare.com/articles/journal_contribution/VEGF-mediated_tight_junctions_pathological_fenestration_enhances_doxorubicin-loaded_glycolipid-like_nanoparticles_traversing_BBB_for_glioblastoma-targeting_therapy/5640157
<p>The existence of blood–brain barrier (BBB) greatly hindered the penetration and accumulation of chemotherapeutics into glioblastoma (GBM), accompany with poor therapeutic effects. The growth of GBM supervene the impairment of tight junctions (TJs); however, the pathogenesis of BBB breakdown in GBM is essentially poorly understood. This study found that vascular endothelial growth factor (VEGF) secreted by GBM cells plays an important role in increasing the permeability of BBB by disrupting endothelial tight junction proteins claudin-5 and thus gave doxorubicin (DOX)-loaded glycolipid-like nanoparticles (Ap-CSSA/DOX), an effective entrance to brain tumor region for GBM-targeting therapy. In addition, VEGF downregulates the expression of claudin-5 with a dose-dependent mode, and interfering with the VEGF/VEGFR pathway using its inhibitor axitinib could reduce the permeability of BBB and enhance the integrity of the barrier. Ap-CSSA/DOX nanoparticles showed high affinity to expressed low-density lipoprotein receptor-related proteins 1 (LRP1) in both BBB and GBM. And BBB pathological fenestration in GBM further exposed more LRP1 binding sites for Ap-CSSA/DOX nanoparticles targeting to brain tumor, resulting in a higher transmembrane transport ratio <i>in vitro</i> and a stronger brain tumor biodistribution <i>in vivo</i>, and finally realizing a considerable antitumor effect. Overall, taking advantage of BBB pathological features to design an appropriate nanodrug delivery system (NDDS) might provide new insights into other central nervous system (CNS) diseases treatment.</p>