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Nanoparticle–Based RNA (siRNA) Combination Therapy Toward Overcoming Drug Resistance in Cancer
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
The major barrier facing siRNA therapeutics is the efficiency of delivery to the desired cell type, tissue, or organ. siRNAs do not readily pass through the cell membrane due to their size and negative charge. Cationic liposome-based strategies are usually used for the cellular delivery of chemically synthesized or in vitro transcribed siRNA [7]. However, there are many problems with lipid-based delivery systems in vivo, such as rapid clearance by the liver and lack of target tissue specificity. Delivery systems can be categorized into physical methods, conjugation methods, and natural carrier (viruses and bacteria) and nonviral carrier methods [8]. DNA-based expression cassettes that express short hairpin RNA (shRNA) are usually delivered to target cells ex vivo by viruses and bacteria, and these modified cells are then reinfused back into the patient [9]. The popular adenovirus- and adeno-associated virus-derived vectors provide efficient delivery for shRNA expression [10]. However, there are problems with delivery using viral vectors, such as insertional mutagenesis and immunogenicity [11]. Nonviral gene delivery systems are highly attractive for gene therapy because they are safer and easier to produce than viral vectors.
Emerging Pulmonary Delivery Strategies in Gene Therapy: State of the Art and Future Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Gabriella Costabile, Olivia M. Merkel
Since the first studies that have shown the potential of using DNA anti-sense oligonucleotides (AON) to modulate target gene expression in the 1970s, the administration of nucleic acids has moved from the concept of a tool for possible drug target identification to an effective therapeutic class (Seguin and Ferrari 2009). In general, there are two main approaches to affect the genetics of targeted cells: (i) gene therapy, where DNA is delivered with the aim of providing a functional copy of a defective gene in the patient, such as double stranded DNA (dsDNA), single stranded (ssDNA), and plasmid DNA or (ii) the delivery of therapeutic nucleic acids which include microRNA (miRNA), short hairpin RNA (shRNA), antisense oligonucleotides (AONs) and small interfering RNA (siRNA). In the case of miRNA, shRNA, and siRNA, the RNA species are processed via the Dicer complex, and loaded into the RNA-induced silencing complex (RISC), which then binds to messenger RNA (mRNA) molecules to either degrade them or modulate their expression. In contrast, AONs are delivered as a single-stranded species and must find their complementary mRNA sequences without the aid of an auxiliary protein (such as Argonaute in the RISC complex). This approach is typically used to target tumors, but can also be used when a genetic disorder results in elevated levels of gene expression (Oliveira et al. 2016).
Gene Therapy and Gene Correction
Published in Yashwant V. Pathak, Gene Delivery Systems, 2022
Manish P. Patel, Sagar A. Popat, Jayvadan K. Patel
Degradation through RNAi: This is a conserved gene regulatory mechanism in which siRNA duplexes are formed by cleavage of long double-stranded RNA (dsRNA) or short hairpin RNA (shRNA) by the dsRNA-specific RNase III enzyme, dicer. The guide strand of the siRNA duplex is assimilated into a nuclease complex which is known as the RNA-induced silencing complex (RISC). The siRNA guides the complex to the complementary target sites within mRNA, which is halved by the RISC component, forming Argonaute2. Argonaute2 is the main component responsible for degradation (Akashi et al. 2005; Rad et al. 2015).
Genetic variants affecting chemical mediated skin immunotoxicity
Published in Journal of Toxicology and Environmental Health, Part B, 2022
Isisdoris Rodrigues de Souza, Patrícia Savio de Araujo-Souza, Daniela Morais Leme
The importance of FLG in preventing skin immune reactions was confirmed by several other in vivo studies. Kawasaki et al. (2012) showed that the skin of FLG-deficient mice exhibited higher antigen penetration, leading to enhanced responses in hapten-induced CHS and higher anti-ovalbumin IgG1 and immunoglobulin E (IgE) serum levels. Moniaga et al. (2010) also reported that FLG-deficient mice developed clinical and histological eczematous skin lesions similar to human AD displaying a defective skin barrier and generating proallergic mice responsive to 1-fluoro-2.4- dinitrobenzene (DNFB) sensitizer and phorbol myristate acetate skin irritant. FLG-deficient mice demonstrate a reduced barrier function with enhanced sensitization to DNFB and skin irritation to croton oil irritant exhibiting increased immune responses (Kawasaki et al. 2012). Dang et al. (2015) using cultured normal human epidermal keratinocytes showed that FLG silencing by short hairpin RNA (shRNA) directly impaired skin barrier function and induced a Th2 immune response, which is recognized as an allergic type of immune response.
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
In 2014, short hairpin RNA (shRNA) mediated RNA interference (RNAi) technology was used to inhibit CK2α expression in Hep-2 laryngeal carcinoma cells. A significant reduction in both mRNA and protein levels of endogenous CK2α was shown in the study. The results also indicated that silencing CK2α resulted in an apoptosis rate of 60% by conducting flow cytometry assay.[42]