Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

Glioblastoma (GBM) is one of the malignant brain tumors with high mortality and no curative treatments. Abnormally elevated vascular endothelial growth factor (VEGF) in GBM seriously disrupts the blood brain barrier (BBB) with an increased permeability, resulting in poor outcome and prognosis. RNAi interference has shown strong potential to inhibit VEGF expression, thus it is necessary to development an effective and safe gene delivery system possessing the ability to cross the BBB and target GBM cells. This study aims to explore the anti-GBM effect of angiopep-2 (Ap) peptide modified reactive oxygen species (ROS) cleavable thioketal (TK) linked glycolipid-like nanocarrier (CSTKSA) delivering anti-VEGF siRNA (R), termed as Ap-CSTKSA/R complexes. Ap functionalized modification produced an enhanced cellular uptake and a stronger bio-distribution of Ap-CSTKSA/R complexes in U87 MG cells and brain tumor tissues, respectively. Ap-CSTKSA/R complexes exhibited great superiority in GBM growth inhibition and finally translated into the longest survival period mainly via receptor-mediated targeting delivery, VEGF gene silencing accompanied with remarkable angiogenesis inhibition, and suppressed expression of caveolin-1 which is involved in BBB functional regulation in the occurrence and treatment of GBM. The study indicated that Ap functionalization on ROS-responsive glycolipid-like copolymer exhibits a promising and effective gene delivery platform for GBM targeted treatment.