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      Gelofusine Attenuates Tubulointerstitial Injury Induced by cRGD-Conjugated siRNA by Regulating the TLR3 Signaling Pathway

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          Abstract

          Integrin αvβ3, which is selectively targeted by cyclic arginine-glycine-aspartic acid (cRGD) peptides, is significantly upregulated in tumors. Previous studies showed that small interfering RNA (siRNA) modified with cRGD (cRGD-siRNA) could significantly inhibit tumor growth through RNAi with oncogene expression. However, cRGD-siRNA is partially reabsorbed and trapped in the kidneys, causing renal injury in an unpredictable manner. This study aimed to investigate the influence of Gelofusine on tubulointerstitial injury induced by cRGD-siRNA in vitro and in vivo. The effect of Gelofusine on the distribution of cRGD-siRNA in tumor-bearing nude mice and wild-type mice was also explored. We found that Gelofusine inhibited apoptosis and activation of the innate immune response of human tubular epithelial cells induced by cRGD-siRNA in vitro. In addition, co-injection of Gelofusine efficiently reduced renal retention of cRGD-siRNA without affecting its tumor targeting in vivo. Further in vivo studies indicated that Gelofusine significantly attenuated tubulointerstitial injury induced by cRGD-siRNA through regulating Toll-like receptor 3 (TLR3)-mediated activation of the nuclear factor κ B (NF-κB) and caspase-3 apoptotic pathway. In conclusion, Gelofusine, acting as a novel and effective renal protective agent, could form a compound preparation with siRNA drugs for future clinical applications.

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          Most cited references40

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          Knocking down barriers: advances in siRNA delivery

          Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.
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            Preclinical and clinical development of siRNA-based therapeutics.

            The discovery of RNA interference, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. Knowledge of the multiple actions of non-coding RNAs has truly allowed viewing DNA, RNA and proteins in novel ways. Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. Despite the potential of siRNAs in cancer therapy, many challenges remain, including rapid degradation, poor cellular uptake and off-target effects. Rational design strategies, selection algorithms, chemical modifications and nanocarriers offer significant opportunities to overcome these challenges. Here, we review the development of siRNAs as therapeutic agents from early design to clinical trial, with special emphasis on the development of EphA2-targeting siRNAs for ovarian cancer treatment.
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              From the RNA world to the clinic.

              The study of RNA has continually emphasized the structural and functional versatility of RNA molecules. This versatility has inspired translational and clinical researchers to explore the utility of RNA-based therapeutic agents for a wide variety of medical applications. Several RNA therapeutics, with diverse modes of action, are being evaluated in large late-stage clinical trials, and many more are in early clinical development. Hundreds of patients are enrolled in large trials testing messenger RNAs to combat cancer, small interfering RNAs to treat renal and hepatic disorders, and aptamers to combat ocular and cardiovascular disease. Results from these studies are generating considerable interest among the biomedical community and the public and will be important for the future development of this emerging class of therapeutic agents.
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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
                14 March 2018
                01 June 2018
                14 March 2018
                : 11
                : 300-311
                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 ]Guangdong Provincial Key Laboratory on Single Cell Technology and Application, Guangzhou, 510515 Guangdong, China
                [4 ]Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510275 Guangdong, China
                [5 ]Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095 Guangdong, China
                [6 ]Department of Pathology, Shenzhen People’s Hospital, Shenzhen, 518020 Guangdong, China
                [7 ]Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
                [8 ]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 Guangdong, China
                [9 ]Guangzhou RiboBio Co., Guangzhou, 510663 Guangdong, China
                Author notes
                []Corresponding author: Aimin Ji, Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282 Guangdong, China.Department of PharmacyZhujiang Hospital of Southern Medical UniversityGuangzhouGuangdong510282China 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.Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China panvictor@ 123456smu.edu.cn
                [∗∗∗ ]Corresponding author: Xiaoxia Liu, Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282 Guangdong, China.Department of PharmacyZhujiang Hospital of Southern Medical UniversityGuangzhouGuangdong510282China 513193168@ 123456qq.com
                [10]

                These author contributed equally to this work.

                Article
                S2162-2531(18)30036-2
                10.1016/j.omtn.2018.03.006
                5889698
                29858065
                63ba4ecc-00b8-4dcf-a5cf-25b8b79230a0
                © 2018 The Authors

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

                History
                : 10 September 2017
                : 10 March 2018
                Categories
                Article

                Molecular medicine
                innate immunity,sirna,toll-like receptor,tubulointerstitial injury,tumor targeting

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