A dual receptor targeting and blood–brain barrier penetrating co-drug-loaded particle mediating inhibition of oxidative phosphorylation for targeted therapy of glioblastoma

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Effective treatment for GBM is limited by the presence of the blood–brain barrier (BBB) and low specificity of tumor targeting. Gboxin is a recently developed drug that effectively inhibits the oxidative phosphorylation of GBM cells, and cannabidiol (CBD) is one kind of cannabinoids showing anti-GBM effects. Herein, a dual receptor-mediated BBB penetrable carrier GZCX co-loaded with Gboxin and CBD was developed for the treatment of GBM. The surface conjugated chlorotoxin (CLTX) facilitated the BBB penetration and GBM targeting, while CBD also promoted the BBB penetration. 10-fold enhanced Gboxin accumulation in the brain was achieved by GZCX. Treatment of GBM-bearing mice with GZCX lead to increased apoptosis and reduced angiogenesis that correlated with a 3.7-fold decrease in tumor burden and corresponding increase in survival. This is the first-time report of 1) the co-delivery of Gboxin and CBD, 2) the integration of CLTX and CBD for BBB penetration and GBM targeting, and 3) the receptor-mediated pathways of BBB penetration of CLTX. This study also offers an example of the highly promising BBB penetrable drug carriers for precise diagnosis and therapy of central nervous system diseases.