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

Publication date: 30 January 2018 Source:International Journal of Pharmaceutics, Volume 536, Issue 1 Author(s): Xuhui Wang, Yue Qiu, Qianwen Yu, Hui Li, Xiaoxiao Chen, Man Li, Yang Long, Yayuan Liu, Libao Lu, Jiajing Tang, Zhirong Zhang, Qin He 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 b...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research