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

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          Abstract

          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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          Angiogenesis in brain tumours.

          Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
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            RNA interference in the clinic: challenges and future directions.

            Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many to consider using RNA interference (RNAi) as a therapeutic approach. Although exploitation of RNAi has immense potential as a cancer therapeutic, many physiological obstacles stand in the way of successful and efficient delivery. This Review explores current challenges to the development of synthetic RNAi-based therapies and considers new approaches to circumvent biological barriers, to avoid intolerable side effects and to achieve controlled and sustained release.
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              Advances in the delivery of RNA therapeutics: from concept to clinical reality

              The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic.
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                Author and article information

                Contributors
                Journal
                Mol Ther Nucleic Acids
                Mol Ther Nucleic Acids
                Molecular Therapy. Nucleic Acids
                American Society of Gene & Cell Therapy
                2162-2531
                06 September 2018
                07 December 2018
                06 September 2018
                : 13
                : 220-232
                Affiliations
                [1 ]Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong, China
                [2 ]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
                [3 ]Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China
                [4 ]Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou 510515, Guangdong, China
                [5 ]Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510275, Guangdong, China
                [6 ]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
                [7 ]Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
                [8 ]Guangzhou RiboBio Co., Guangzhou 510663, Guangdong, China
                [9 ]Department of Hepatobiliary Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong, China
                [10 ]Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
                [11 ]Department of Orthopaedic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou 510515, Guangdong, China
                Author notes
                []Corresponding author: Aimin Ji, Department of Pharmacy, Zhujiang Hospital of Southern Medical University, 253 Industry Avenue, Guangzhou 510282, Guangdong, China. aiminji_007@ 123456163.com
                [∗∗ ]Corresponding author: Xinghua Pan, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. panvictor@ 123456smu.edu.cn
                [∗∗∗ ]Corresponding author: Yawei Yuan, Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China. yuanyawei2015@ 123456outlook.com
                [12]

                These authors contributed equally to this work.

                Article
                S2162-2531(18)30241-5
                10.1016/j.omtn.2018.09.002
                6178240
                30312846
                06135ffe-2b2a-488a-93b1-41f35841e701
                © 2018 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 30 July 2018
                : 4 September 2018
                Categories
                Article

                Molecular medicine
                sirna delivery,gene silencing,orthotopic glioblastoma,tumor targeting
                Molecular medicine
                sirna delivery, gene silencing, orthotopic glioblastoma, tumor targeting

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