Autophagy inhibition changes the disposition of non-viral gene carriers during blood-brain barrier penetration and enhances TRAIL-induced apoptosis in brain metastatic tumor.,Journal of Controlled Release

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Autophagy inhibition changes the disposition of non-viral gene carriers during blood-brain barrier penetration and enhances TRAIL-induced apoptosis in brain metastatic tumor.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-02-26 , DOI: 10.1016/j.jconrel.2020.02.042
Xuhui Wang ₁ , Sheng Yin ₁ , Man Li ₁ , Jingdong Rao ₁ , Dandan Wan ₁ , Yue Qiu ₁ , Qianwen Yu ₁ , Xiaoxiao Chen ₁ , Zhengze Lu ₁ , Yang Long ₁ , Zhirong Zhang ₁ , Qin He ₁

Affiliation

Non-viral gene delivery systems have proven to be a promising approach in the treatment of brain metastatic cancers but facing delivery difficulties. Due to the existence of blood-brain barrier, non-viral gene carriers must pass through brain capillary endothelial cells to accumulate at the brain tumor sites. However, during this process, most of them trap into brain capillary endothelial cells and fail to penetrate to the brain tumor sites. Autophagy is involved in dynamic disposition of both intracellular and extracellular components, which theoretically affects intracellular fate of non-viral gene carriers during BBB penetration. In the present study, R6dGR peptide-modified PEGylated polyethyleneimine that carry therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (PPR/pTRAIL) are established as model non-viral gene delivery system and applied in breast cancer brain metastasis therapy. Autophagy-mediated lysosome degradation pathway is found to be involved in the degradation of PPR/pTRAIL in brain capillary endothelial cells and prevents them from BBB penetration. Pre-inhibiting BBB autophagy level by wortmannin loaded liposomes (Wtmn-Lip) can increase brain accumulation of non-viral gene carrier PPR without damaging BBB tight junctions. Besides, Wtmn-Lip synergistically induces apoptosis with TRAIL via different signaling pathways. Herein, pre-treatment of Wtmn-Lip might solve delivery difficulties of non-viral gene carriers in the treatment of brain metastatic cancers.

中文翻译：

自噬抑制作用改变血脑屏障穿透过程中非病毒基因载体的配置，并增强TRAIL诱导的脑转移性肿瘤的凋亡。

非病毒基因传递系统已被证明是治疗脑转移癌的一种有前途的方法，但面临传递困难。由于存在血脑屏障，非病毒基因载体必须穿过脑毛细血管内皮细胞才能积聚在脑肿瘤部位。然而，在此过程中，它们中的大多数会陷入脑毛细血管内皮细胞，并且无法渗透到脑肿瘤部位。自噬参与细胞内和细胞外成分的动态处置，这在理论上影响BBB穿透过程中非病毒基因载体的细胞内命运。在目前的研究中，携带编码人肿瘤坏死因子相关凋亡诱导配体（PPR / pTRAIL）的治疗基因的R6dGR肽修饰的PEG化聚乙烯亚胺被建立为模型非病毒基因递送系统，并用于乳腺癌脑转移治疗。发现自噬介导的溶酶体降解途径与脑毛细血管内皮细胞中PPR / pTRAIL的降解有关，并阻止它们从BBB渗透。渥曼青霉素负载脂质体（Wtmn-Lip）预先抑制BBB自噬水平可以增加非病毒基因载体PPR的大脑积累，而不会破坏BBB紧密连接。此外，Wtmn-Lip通过不同的信号通路与TRAIL协同诱导细胞凋亡。在这里

更新日期：2020-02-27

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