Enhanced glioma therapy by synergistic inhibition of autophagy and tyrosine kinase activity.
Enhanced glioma therapy by synergistic inhibition of autophagy and tyrosine kinase activity.
复制标题
DOI：
10.1016/j.ijpharm.2017.09.007
复制
发表时间：
2018-01
影响因子：
5.8
通讯作者：
Xuhui Wang;Yue Qiu;Qianwen Yu;Hui Li;Xiaoxiao Chen;Man Li;Yang Long;Yayuan Liu;Libao Lu
中科院分区：
文献类型：
--
作者：
Xuhui Wang;Yue Qiu;Qianwen Yu;Hui Li;Xiaoxiao Chen;Man Li;Yang Long;Yayuan Liu;Libao Lu
自噬是一种溶酶体降解途径，作为一种细胞保护机制，导致各种癌细胞产生治疗耐药。最近的研究表明，羟氯喹可以抑制自噬的后一步，从而增强酪氨酸酶抑制剂ZD6474的抗胶质瘤作用。然而，ZD6474在体内的非选择性分布以及羟基氯喹通过血脑屏障的低渗透性限制了其在脑胶质瘤治疗中的临床应用。在这里，我们将ZD6474和羟氯喹共包裹到R6dGR多肽修饰脂质体(R6dGR-LIP)中，该脂质体能够特异性识别内皮细胞和胶质瘤细胞上高表达的整合素αvβ3和神经粘连蛋白-1受体。R6dGR显著增强了脑靶向性，克服了血脑屏障。我们的结果证实，在R6dGR-Lip中负载羟基氯喹比游离羟基氯喹更有效地阻断胶质瘤细胞的自噬通量，并在体内外显著地增敏胶质瘤细胞对ZD6474诱导的细胞死亡。共包裹的R6dGR修饰脂质体(ZD6474/HCQ-R6dGR-Lip)与ZD6474-R6dGR-Lip相比延长了C6脑胶质瘤小鼠的中位存活时间1.2倍，与游离ZD6474/HCQ相比延长了1.5倍，与游离ZD6474相比延长了1.8倍，显示出协同治疗作用。因此，ZD6474/HCQ-R6dGR-Lip被认为是一种潜在的策略，可以进一步用于有效的抗胶质瘤治疗。
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 ZD6474in vivoand 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 deathin vitroandin 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.