Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China.
J Nanobiotechnology. 2024 Aug 20;22(1):495. doi: 10.1186/s12951-024-02776-y.
The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree.
In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects.
Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
Hippo 通路是一条保守的肿瘤抑制信号通路，其失调通常与异常细胞生长和肿瘤发生有关。我们之前揭示了转录共激活因子 Yes 相关蛋白（YAP），Hippo 通路的关键效应因子，是胶质母细胞瘤（GBM）的一个分子靶点，GBM 是最常见的恶性脑肿瘤。用小干扰 RNA（siYAP）或特异性抑制剂verteporfin（VP）抑制 YAP 可以在一定程度上减少 GBM 的生长。
在这项研究中，为了增强 siYAP 和 VP 的抗 GBM 作用，我们设计了逐步靶向和缺氧反应性脂质体（AMVY@NPs），它包裹了缺氧反应性多甲硝唑涂层的 VP 和 DOTAP 吸附的 siYAP，并在表面进行了血管生成肽-2（A2）修饰。AMVY@NPs 表现出优异的血脑屏障穿透性、GBM 靶向性、缺氧反应性和高效 siYAP 和 VP 释放特性。通过抑制 YAP 的表达和功能，AMVY@NPs 协同抑制了体外 GBM 的生长和干性。此外，AMVY@NPs 强烈抑制了 U87 原位异种移植瘤的生长，提高了荷瘤小鼠的存活率，没有不良影响。
用携带 siYAP 和 VP 的逐步靶向和缺氧反应性脂质体 AMVY@NPs 特异性靶向 YAP，有效地抑制了 GBM 的进展。这项研究为未来 GBM 的分子靶向治疗提供了有价值的药物递送平台和创新思路。
