An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo

作者：Cen, Bohong; Wei, Yuanyi; Huang, Wen; Teng, Muzhou; He, Shuai; Li, Jianlong; Wang, Wei; He, Guolin; Bai, Xin; Liu, Xiaoxia; Yuan, Yawei^*; Pan, Xinghua^*; Ji, Aimin^*

来源：Molecular Therapy - Nucleic Acids, 2018, 13: 220-232.

DOI：10.1016/j.omtn.2018.09.002

• SMALL INTERFERING RNA
• CHEMICAL-MODIFICATION
• VASCULOGENIC MIMICRY
• POLYMERIC MICELLES
• DRUG-DELIVERY
• RGD DIMERS
• BRAIN
• TUMOR
• GLIOMA
• CELLS

The PI3K-AKT-mTOR-signaling pathway is frequently activated in glioblastoma (GBM). Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)/p110 beta (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 alpha nu beta 3 receptors. The alpha nu beta 3-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 antitumor efficacy of biRGD-siPIK3CB. In vitro, biRGD-siPIK3CB specifically entered and silenced PIK3CB expression in GBM cells in an alpha nu beta 3 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.

• 出版日期2018-12-7
• 单位南方医科大学; 广州医科大学; 中山大学