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Nanotechnologies Assemblies of siRNA and Chemotherapeutic Drugs Codelivered for Cancer Therapeutic Applications
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
For targeted therapy, in addition to monoclonal antibodies used in the clinic, such as bevacizumab (Avastin®) and ziv-aflibercept (Zaltrap®) [158,159] that binding to vascular endothelial growth factor (VEGF) and inhibiting tumor angiogenesis, anti-VEGF siRNA exhibits great potential for inhibition of angiogenesis [160,161]. siRNAs are specifically short dsRNA fragments of 19–25 base-pairs that can incorporate into an RISC to silence a target mRNA in a sequence-specific manner. However, many critical hurdles remain for in vivo application of siRNA as a feasible therapeutic, including poor biostability, poor cellular uptake, and activation of the immune response. In particular, if siRNA is exposed to the plasma or other protein-rich biological media, it becomes very unstable and is quickly degraded by nucleases, leading to poor transfection efficiency. To enhance the efficiency of in vivo siRNA delivery, delivery systems, including viral and nonviral vectors, have been developed. Viral vectors can achieve highly efficient gene transfer but have the risk of causing undesired immune stimulation [162]. In contrast, nonviral vectors such as cationic polymer- or micelle-based carriers (“polyplexes” or “micelleplexes”) [163] and liposomes have been reported as good siRNA carriers that can suppress expression of target genes with very little immunotoxicity [164]. And polymers such as polyethylene glycol (PEG) can be conjugated to siRNA to further improve its stability and prolong its blood circulation time after intravenous (i.v) administration [165,166].
Lipid Nanoparticle Induced Immunomodulatory Effects of siRNA
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Ranjita Shegokar, Prabhat Mishra
RNAi was first observed by plant biologists in the late 1980s [4], although their molecular structure remained unclear until the 1990s [4]. Later studies in the nematode Caenorhabditis elegans exhibited the gene-silencing mechanism [5]. The biology and mechanisms of actions of RNAi have been extensively reviewed thereafter [6–8]. siRNA can regulate gene expression by inhibiting the synthesis of the encoded protein in natural ways. Tabara et al. [9] concluded that transposon silencing is one of the natural functions of RNAi. RNAi techniques were quantitatively more efficient and more durable in cell culture compared with the antisense technology [10, 11]. One major advantage of RNAi over antisense oligonucleotides is that siRNA is based on a catalytic mechanism. Bertrand et al. [12, 13] concluded that siRNA is very efficient in inhibiting the synthesis of target proteins with improved specificity and reduced dose by 100-to 1000-fold.
Glossary of scientific and technical terms in bioengineering and biological engineering
Published in Megh R. Goyal, Scientific and Technical Terms in Bioengineering and Biological Engineering, 2018
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules, 20-25 base pairs in length. The siRNA plays many roles, but it is most notable in the RNA interference (RNAi) pathway, where it interferes with the expression of specific genes with complementary nucleotide sequences. siRNA functions by causing mRNA to be broken down after transcription, resulting in no translation. siRNA also acts in RNAi-related pathways, e.g., as an antiviral mechanism or in shaping the chromatin structure of a genome.
Lipid-based liquid crystalline films and solutions for the delivery of cargo to cells
Published in Liquid Crystals Reviews, 2019
Marilyn Porras-Gomez, Cecilia Leal
The delivery of nucleic acids into the cytosol has become a growing field in biomedicine [9,22,24,27,35,42,44–51]. siRNA is a class of double stranded short (ribo)nucleic acids (21-23 nucleotides long) capable of achieving gene knockdown (i.e. silenced or decreased gene expression) in eukaryotic cells. The clinical potential of siRNA in diseases such as cancer, neurodegenerative disorders and viral infectious diseases has been amply shown [52]. DNA depends upon entering the nucleus to initiate the transfection process. In contrast, siRNA does not require entering the nucleus: once it enters the cytosol, it is incorporated into a protein complex that finds and destroys target messenger RNA, which further propagates gene silencing [53,54]. Naked siRNA has shown silencing efficiency but is prone to enzymatic degradation and its negative charge prevents it to easily enter the cytosol. The design of non-cytotoxic carriers that deliver siRNA in a localised manner [49] and provide further specificity to gene silencing has become a critical challenge for the development of better therapies. Various lipid-nucleic acid complexes have been developed in order to address some of these issues and in this paper we describe a few examples [10,15,21,22,42,43,51,55,56].
Synthesis of PEGylated cationic curdlan derivatives with enhanced biocompatibility
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Muqier Muqier, Hai Xiao, Xiang Yu, Yifeng Li, Mingming Bao, Qingming Bao, Shuqin Han, Huricha Baigude
To solve these problems, researchers have explored a variety of methods like chemical modification of siRNA [14–16] and utilization of delivery systems [17, 18]. While the stability of chemically modified siRNA was remarkably enhanced in vivo [19, 20], increased toxicity and reduction of gene silencing were also observed [21, 22]. Although the present approaches can successfully target liver, lack of highly efficient delivery system that can target tissues and organs other than liver remains a major challenge in converting therapeutic siRNA into more clinical applications. The non-viral vectors have been widely studied for tissue specific siRNA delivery due to the flexibility for ligand functionalization, low immunogenicity [23] and low production cost [24].
Preparation and characterization of novel albumin-sericin nanoparticles as siRNA delivery vehicle for laryngeal cancer treatment
Published in Preparative Biochemistry and Biotechnology, 2019
Eda Yalcin, Goknur Kara, Ekin Celik, Ferda Alpaslan Pinarli, Guleser Saylam, Ceren Sucularli, Serhat Ozturk, Esin Yilmaz, Omer Bayir, Mehmet Hakan Korkmaz, Emir Baki Denkbas
RNA interference (RNAi) has become a widely used powerful tool in gene functional analyses and therapeutic applications since it has first emerged as a post-transcriptional gene silencing strategy in 1998.[1,2] This process provides sequence-specific degradation of the target mRNA and hence inhibits translation of the target protein via the key role of siRNA. In this mechanism, the double-stranded RNAs (dsRNAs) are cleaved by the enzyme called Dicer and divided into fragments of 21–23 nucleotides which are called siRNAs. These siRNAs, consisting of a passenger strand and a guide strand, bind to the RNA-Induced Silencing Complex (RISC). Subsequently, the guide strand is complementarily directed to the target mRNA by the activity of Argonaute-2 enzyme to cleave between the 10th and 11th bases of the mRNA.[3] siRNAs can be also produced synthetically with unique sequences that are highly specific to the target. siRNAs have been studied commonly for cancer treatment owing to their high potency for gene silencing.[4] Despite this great potential, a number of drawbacks must be considered for its therapeutic use. The difficulty in delivery of the siRNA molecule to the targeted area resulting from its rapid enzymatic degradation and insufficient cellular uptake is the major obstacle.[4] Therefore, an efficient carrier is still a need in siRNA therapies, and lately, nanoparticles have come forward as favorable delivery systems for safe siRNA transportation and accomplishment of effective gene knockdown in targeted cells.