An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo
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. Howeve...
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| Main Authors: | , , , , , , , , , , , , |
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Elsevier,
2018-12-01T00:00:00Z.
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|---|---|---|---|
| 001 | doaj_a64c112b0f8e48d3b7e3542fd841ec7c | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Bohong Cen |e author |
| 700 | 1 | 0 | |a Yuanyi Wei |e author |
| 700 | 1 | 0 | |a Wen Huang |e author |
| 700 | 1 | 0 | |a Muzhou Teng |e author |
| 700 | 1 | 0 | |a Shuai He |e author |
| 700 | 1 | 0 | |a Jianlong Li |e author |
| 700 | 1 | 0 | |a Wei Wang |e author |
| 700 | 1 | 0 | |a Guolin He |e author |
| 700 | 1 | 0 | |a Xin Bai |e author |
| 700 | 1 | 0 | |a Xiaoxia Liu |e author |
| 700 | 1 | 0 | |a Yawei Yuan |e author |
| 700 | 1 | 0 | |a Xinghua Pan |e author |
| 700 | 1 | 0 | |a Aimin Ji |e author |
| 245 | 0 | 0 | |a An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo |
| 260 | |b Elsevier, |c 2018-12-01T00:00:00Z. | ||
| 500 | |a 2162-2531 | ||
| 500 | |a 10.1016/j.omtn.2018.09.002 | ||
| 520 | |a 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. Keywords: siRNA delivery, gene silencing, orthotopic glioblastoma, tumor targeting | ||
| 546 | |a EN | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Molecular Therapy: Nucleic Acids, Vol 13, Iss , Pp 220-232 (2018) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2162253118302415 | |
| 787 | 0 | |n https://doaj.org/toc/2162-2531 | |
| 856 | 4 | 1 | |u https://doaj.org/article/a64c112b0f8e48d3b7e3542fd841ec7c |z Connect to this object online. |