VEGF-mediated tight junctions pathological fenestration enhances doxorubicin-loaded glycolipid-like nanoparticles traversing BBB for glioblastoma-targeting therapy.

Abstract

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 in vitro and a stronger brain tumor biodistribution in vivo, 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.

• Authors: Lijuan Wen, Yanan Tan, Suhuan Dai, Yun Zhu, Tingting Meng, Xiqin Yang, Yupeng Liu, Xuan Liu, Hong Yuan, Fuqiang Hu
• Journal: Drug delivery (Drug Deliv) Vol. 24 Issue 1 Pg. 1843-1855 (Nov 2017) ISSN: 1521-0464 [Electronic] England
• PMID: 29182025 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Glycolipids
• Vascular Endothelial Growth Factor A
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blood-Brain Barrier (metabolism)
• Brain (drug effects, metabolism)
• Brain Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Glioblastoma (drug therapy, metabolism)
• Glycolipids (administration & dosage)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (administration & dosage)
• Permeability (drug effects)
• Tight Junctions (metabolism)
• Tissue Distribution
• Vascular Endothelial Growth Factor A (metabolism)