Henan-Macquarie University Joint Centre for Biomedical Innovation School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China.
Centre for Motor Neuron Disease Research, Department of Biomedical Sciences Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
Adv Mater. 2020 Jun;32(24):e2000416. doi: 10.1002/adma.202000416. Epub 2020 May 6.
Small interfering RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy methods. However, siRNA-based GBM therapy is seriously hampered by a number of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood-brain barrier (BBB) penetration, and tumor accumulation, as well as inefficient siRNA intracellular release. Herein, an Angiopep-2 (Ang) functionalized intracellular-environment-responsive siRNA nanocapsule (Ang-NC (siRNA)) is successfully developed as a safe and efficient RNAi agent to boost siRNA-based GBM therapy. The experimental results demonstrate that the developed Ang-NC (siRNA) displays long circulation in plasma, efficient BBB penetration capability, and GBM accumulation and retention, as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular-environment-responsive siRNA release. Such superior properties of Ang-NC (siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.
小干扰 RNA（siRNA）被认为是治疗人类癌症的一种极具前途的治疗剂，包括胶质母细胞瘤（GBM），这是一种致命的疾病，没有有效的治疗方法。然而，基于 siRNA 的 GBM 治疗受到多种挑战的严重阻碍，包括 siRNA 脑内递送的稳定性差、血液循环时间短、血脑屏障（BBB）穿透率低、肿瘤蓄积以及 siRNA 细胞内释放效率低。在此，成功开发了一种载有 Angiopep-2（Ang）的细胞内环境响应性 siRNA 纳米胶囊（Ang-NC（siRNA）），作为一种安全有效的 RNAi 试剂，以增强基于 siRNA 的 GBM 治疗。实验结果表明，所开发的 Ang-NC（siRNA）在血浆中具有长循环、高效的 BBB 穿透能力和 GBM 蓄积和保留能力，以及响应性细胞内 siRNA 释放，这归因于其独特的设计，即具有聚合物壳的小尺寸（25nm），可保护 siRNA、Ang 功能化用于 BBB 穿越和 GBM 靶向，以及二硫键作为细胞内环境响应性 siRNA 释放的连接体。Ang-NC（siRNA）的这些优越特性导致对原位 U87MG 异种移植的显著生长抑制而没有引起不良反应，实现了显著改善的生存获益。所开发的 siRNA 纳米胶囊为 GBM 及其他疾病的 RNAi 治疗提供了一种新策略。
