The PI3K-AKT-mTOR-signaling pathway is frequently activated in glioblastoma (GBM). Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)/p110β (a PI3K catalytic isoform) by RNAi substantially suppresses GBM growth with less toxicity to normal astrocytes. However, insufficient and non-specific small interfering RNA (siRNA) delivery may limit the efficacy of RNAi-based therapies against GBM. Here we prepared a novel methoxy-modified PIK3CB siRNA molecule (siPIK3CB) that was covalently conjugated to a [cyclo(Arg-Gly-Asp-D-Phe-Lys)-Ahx]₂-Glu-PEG-MAL (biRGD) peptide, which selectively binds to integrin αvβ3 receptors. The αvβ3-positive U87MG cell line was selected as a representative for GBM. An orthotopic GBM xenograft model based on luciferase-expressing U87MG was established and validated in vivo to investigate bio-distribution and anti-tumor efficacy of biRGD-siPIK3CB. In vitro, biRGD-siPIK3CB specifically entered and silenced PIK3CB expression in GBM cells in an αvβ3 receptor-dependent manner, thus inhibiting cell cycle progression and migration and enhancing apoptosis. In vivo, intravenously injected biRGD-siPIK3CB substantially slowed GBM growth and prolonged survival by reducing tumor viability with silencing PIK3CB expression. Furthermore, biRGD-siPIK3CB led to mild tubulointerstitial injury in the treatment of GBM without obvious hepatotoxicity, whereas co-infusion of Gelofusine obviously alleviated this injury without compromising anti-tumor efficacy. These findings revealed a great translational potential of biRGD-siPIK3CB conjugate as a novel molecule for GBM therapy.

PI3K-AKT-mTOR信号通路在胶质母细胞瘤（GBM）中经常被激活。RNAi抑制磷脂酰肌醇-4,5-双磷酸3-激酶催化亚基β（PIK3CB）/p110β（PI3K催化亚型）基本上抑制了GBM的生长，对正常星形胶质细胞的毒性较小。但是，不足和非特异性的小干扰RNA（siRNA）传递可能会限制基于RNAi的抗GBM疗法的疗效。在这里，我们准备了一个新的甲氧基修饰的PIK3CB siRNA分子（siPIK3CB），它与[cyclo（Arg-Gly-Asp-D-Phe-Lys）-Ahx] ₂共价结合。-Glu-PEG-MAL（biRGD）肽，选择性结合整联蛋白αvβ3受体。选择αvβ3阳性的U87MG细胞系作为GBM的代表。建立了基于表达荧光素酶的U87MG的原位GBM异种移植模型，并在体内进行了验证，以研究biRGD-siPIK3CB的生物分布和抗肿瘤功效。在体外，biRGD-siPIK3CB以依赖于αvβ3受体的方式特异性进入GBM细胞并使其沉默，从而抑制PIK3CB的表达，从而抑制细胞周期进程和迁移并增强细胞凋亡。体内因此，静脉注射biRGD-siPIK3CB可通过沉默PIK3CB表达降低肿瘤生存力，从而显着减慢GBM的生长并延长生存期。此外，biRGD-siPIK3CB在治疗GBM时导致轻度肾小管间质损伤，而没有明显的肝毒性，而共注入明索夫碱则明显减轻了这种损伤，而没有损害抗肿瘤功效。这些发现揭示了biRGD-siPIK3CB缀合物作为GBM治疗的新分子具有巨大的翻译潜力。