Protein Toxin Chaperoned by LRP-1-Targeted Virus-Mimicking Vesicles Induces High-Efficiency Glioblastoma Therapy In Vivo
Protein Toxin Chaperoned by LRP-1-Targeted Virus-Mimicking Vesicles Induces High-Efficiency Glioblastoma Therapy In Vivo
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DOI：
10.1002/adma.201800316
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发表时间：
2018-07-26
影响因子：
29.4
通讯作者：
Zhong, Zhiyuan
中科院分区：
文献类型：
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作者：
Jiang, Yu;Yang, Weijing;Zhong, Zhiyuan
胶质母细胞瘤是一种最难治和高死亡率的恶性肿瘤，因为它的极低的药物可及性导致的血脑屏障（BBB）。在此，据报道，血管肽素-2导向的和氧化还原响应的病毒模拟聚合物囊泡（ANG-PS）（血管肽素-2是靶向低密度脂蛋白受体相关蛋白-1（LRP-1）的肽）可以有效地和选择性地伴侣皂草素（SAP），一种高效的天然蛋白质毒素，在裸鼠中原位人胶质母细胞瘤异种移植物。与化学治疗剂不同，游离SAP具有低细胞毒性。然而，SAP负载的ANG-PS在体外对U-87 MG人胶质母细胞瘤细胞显示出惊人的抗肿瘤活性（半最大抑制浓度，IC 50 = 30.2 × 10（-9）m），以及在体内高BBB转胞吞作用和胶质母细胞瘤蓄积。SAP负载的ANG-PS全身给药于U-87 MG原位人胶质母细胞瘤荷瘤小鼠，副作用小，有效抑制肿瘤，并显著提高存活率。由LRP-1靶向的病毒模拟囊泡陪伴的蛋白质毒素成为胶质母细胞瘤的一种新的和非常有前途的治疗方式。
Glioblastoma is a most intractable and high-mortality malignancy because of its extremely low drug accessibility resulting from the blood-brain barrier (BBB). Here, it is reported that angiopep-2-directed and redox-responsive virus-mimicking polymersomes (ANG-PS) (angiopep-2 is a peptide targeting to low-density lipoprotein receptor-related protein-1 (LRP-1)) can efficiently and selectively chaperone saporin (SAP), a highly potent natural protein toxin, to orthotopic human glioblastoma xenografts in nude mice. Unlike chemotherapeutics, free SAP has a low cytotoxicity. SAP-loaded ANG-PS displays, however, a striking antitumor activity (half-maximal inhibitory concentration, IC50= 30.2 x 10(-9)m) toward U-87 MG human glioblastoma cells in vitro as well as high BBB transcytosis and glioblastoma accumulation in vivo. The systemic administration of SAP-loaded ANG-PS to U-87 MG orthotopic human-glioblastoma-bearing mice brings about little side effects, effective tumor inhibition, and significantly improved survival rate. The protein toxins chaperoned by LRP-1-targeted virus-mimicking vesicles emerge as a novel and highly promising treatment modality for glioblastoma.