An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo.
An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo.
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一种有效的二价环状 RGD-PIK3CB siRNA 缀合物，用于体外和体内针对胶质母细胞瘤的特异性靶向治疗
DOI：
10.1016/j.omtn.2018.09.002
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Ji A
中科院分区：
文献类型：
--
作者：
Cen B;Wei Y;Huang W;Teng M;He S;Li J;Wang W;He G;Bai X;Liu X;Yuan Y;Pan X;Ji A
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-4,5-二磷酸3-激酶催化亚基β (PIK3CB)/p110β （PI3K催化异构体）可显著抑制GBM生长，对正常星形细胞的毒性较小。然而，不充分和非特异性的小干扰RNA （siRNA）递送可能会限制基于rnai治疗GBM的疗效。本研究制备了一种新的甲氧基修饰的PIK3CB siRNA分子（siPIK3CB），该分子与[cyclo(arg - gly - asp - d - ph - lys)-Ahx]2-Glu-PEG-MAL （biRGD）肽共价偶联，可选择性结合整联素αv - β3受体。选择αvβ3阳性的U87MG细胞系作为GBM的代表。建立基于表达U87MG荧光素酶的原位GBM异种移植模型并进行体内验证，研究biRGD-siPIK3CB的生物分布及抗肿瘤效果。在体外，biRGD-siPIK3CB以αvβ3受体依赖的方式特异性进入GBM细胞并沉默PIK3CB的表达，从而抑制细胞周期进展和迁移，促进细胞凋亡。在体内，静脉注射biRGD-siPIK3CB通过沉默PIK3CB表达来降低肿瘤活力，从而显著减缓GBM的生长并延长生存期。此外，biRGD-siPIK3CB在治疗GBM时导致轻度的小管间质损伤，无明显的肝毒性，而联合输注Gelofusine可明显减轻这种损伤，且不影响抗肿瘤效果。这些发现揭示了biRGD-siPIK3CB偶联物作为治疗GBM的新分子具有巨大的翻译潜力。
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.
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影响因子：
14.9
作者：
Elkayam E;Parmar R;Brown CR;Willoughby JL;Theile CS;Manoharan M;Joshua-Tor L
通讯作者：
Joshua-Tor L
影响因子：
4.7
作者：
Alam, Md Rowshon;Ming, Xin;Fisher, Michael;Lackey, Jeremy G.;Rajeev, Kallanthottathil G.;Manoharan, Muthiah;Juliano, Rudy L.
通讯作者：
Juliano, Rudy L.
DOI：
10.1016/j.omtn.2017.06.005
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chakraborty C;Sharma AR;Sharma G;Doss CGP;Lee SS
通讯作者：
Lee SS
肿瘤靶向 cRGD-EGFR siRNA 缀合物及其对胶质母细胞瘤的体外和体内抗肿瘤作用
影响因子：
6
作者：
He S;Cen B;Liao L;Wang Z;Qin Y;Wu Z;Liao W;Zhang Z;Ji A
通讯作者：
Ji A
影响因子：
4.7
作者：
Liu S
通讯作者：
Liu S