Enhanced glioma therapy by synergistic inhibition of autophagy and tyrosine kinase activity

Abstract

Autophagy is a lysosomal degradation pathway that acts as a cytoprotective mechanism causing treatment resistance in various cancer cells. Recent studies showed that hydroxychloroquine can inhibit the latter step of autophagy and therefore enhance the anti-glioma efficiency of ZD6474, a tyrosine kinase inhibitor. However, the nonselective distribution of ZD6474 in vivo and the low penetrating ability of hydroxychloroquine when crossing the blood-brain barrier restrict their clinical use in glioma therapy. Here we coencapsulated ZD6474 and hydroxychloroquine into R6dGR peptide-modified liposomes (R6dGR-Lip) which can specifically recognize both integrin αvβ3 and neuropilin-1 receptors that are highly expressed on the endothelial cells and glioma cells. R6dGR significantly enhanced the brain targeting and overcame the blood-brain barrier. Our results confirmed that loading hydroxychloroquine into R6dGR-Lip blocked autophagic flux more efficiently than free hydroxychloroquine in glioma cells and significantly sensitized glioma cells to ZD6474-induced cell death in vitro and in vivo. The coencapsulated R6dGR-modified liposomes (ZD6474/HCQ-R6dGR-Lip) prolonged the medium survival time of intracranial C6 glioma bearing mice by 1.2-fold compared with ZD6474-R6dGR-Lip, 1.5-fold compared with free ZD6474/HCQ, and 1.8-fold compared with free ZD6474, exhibiting a synergistic therapeutic effect. Therefore, ZD6474/HCQ-R6dGR-Lip is presented as a potential strategy which could be further used for efficient anti-glioma therapy.

Keywords: Anti-glioma; Autophagy inhibition; Combination therapy; Drugs coencapsulated liposomes; Hydroxychloroquine; ZD6474.