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>