Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Department of Neurological Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, China.
Nat Commun. 2017 May 10;8:15144. doi: 10.1038/ncomms15144.
Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to 'drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.
高活性 Ras 调节多种人类恶性肿瘤中的致癌途径，包括神经胶质瘤，是癌症治疗的一个有吸引力的靶点。癌细胞中的 Ras 激活通过巨胞饮作用驱动蛋白质内化，这是一种关键的营养获取过程。通过利用这种独特的内吞途径，我们在这里创建了一种受生物启发的纳米结构，它可以诱导癌细胞“喝药”，以靶向激活转录因子-5（ATF5），这是神经胶质瘤中过度表达的抗细胞凋亡转录因子。载有 siRNA 的载脂蛋白 E3 重构的高密度脂蛋白被用来包裹负载钙磷核心的 siRNA，并促进其穿透血脑屏障，从而以巨胞饮作用依赖的方式靶向神经胶质瘤细胞。携带 ATF5 siRNA 的纳米结构在体外和异种移植肿瘤模型中均表现出显著的 RNA 干扰效率，增加神经胶质瘤细胞凋亡并抑制肿瘤细胞生长。这种针对 Ras 激活引起的巨胞饮作用的靶向策略为神经胶质瘤和其他 Ras 激活型癌症的精准治疗提供了一种基于纳米颗粒的方法。
