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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

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      Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach

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          Abstract

          Cancer is one of the most complex diseases that has resulted in multiple genetic disorders and cellular abnormalities. Globally, cancer is the most common health concern disease that is affecting human beings. Great efforts have been made over the past decades in biology with the aim of searching novel and more efficient tools in therapy. Thus, small interfering RNAs (siRNAs) have been considered one of the most noteworthy developments which are able to regulate gene expression following a process known as RNA interference (RNAi). RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer. However, siRNA therapeutics have to face important drawbacks in therapy including stability and successful siRNA delivery in vivo. In this regard, the development of effective siRNA delivery systems has helped addressing these issues by opening novel therapeutic windows which have allowed to build up important advances in Nanomedicine. In this review, we discuss the progress of siRNA therapy as well as its medical application via nanoparticle-mediated delivery for cancer treatment.

          Most cited references153

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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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            New Developments in Liposomal Drug Delivery.

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              Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery

              Nanoparticles are employed for delivering therapeutics into cells 1,2 . However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell specific internalization, excretion, toxicity, and efficacy 3-7 . A variety of materials have been explored for delivering small interfering RNAs (siRNAs) - a therapeutic agent that suppresses the expression of targeted genes 8,9 . However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, lack of tissue specificity and potential toxicity 10-12 . Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer targeting ligands (such as peptides and folate) on the nanoparticle surface can be precisely controlled. We show that at least three folate molecules per nanoparticle is required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ∼ 24.2 min) than the parent siRNA (t1/2 ∼ 6 min).
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                IJN
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                02 May 2019
                2019
                : 14
                : 3111-3128
                Affiliations
                [1 ]Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science , Tehran, Iran
                [2 ]Department of Biology, Damghan Branch, Islamic Azad University , Damghan, Iran
                [3 ]Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona 08034, Spain
                [4 ]Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER BBN) , Madrid, Spain
                [5 ]Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center , Houston, TX, USA
                [6 ]Department of GI Medical Oncology, University of Texas, M.D. Anderson Cancer Center , Houston, TX, USA
                [7 ]Department of Biology, Zabol University , Zabol, Iran
                Author notes
                Correspondence: Fereidoon Memari; Seyed Rohollah MiriCancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science , Tehran, IranEmail memarife@ 123456tums.ac.ir ; Srmiri@ 123456sina.tums.ac.ir
                [*]

                These authors contributed equally to this work

                Article
                200253
                10.2147/IJN.S200253
                6504672
                31118626
                2132cde0-2709-4a12-b171-6f50570efb3a
                © 2019 Mahmoodi Chalbatani et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 January 2019
                : 23 March 2019
                Page count
                Figures: 5, Tables: 3, References: 183, Pages: 18
                Categories
                Review

                Molecular medicine
                delivery strategies,lipoplexes,nanovectors,polymeric nanoparticles,sirna
                Molecular medicine
                delivery strategies, lipoplexes, nanovectors, polymeric nanoparticles, sirna

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