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MicroRNAs in Human Cancers and Therapeutic Applications
Published in Peixuan Guo, Kirill A. Afonin, RNA Nanotechnology and Therapeutics, 2022
Ji Young Yoo, Balveen Kaur, Tae Jin Lee, Peixuan Guo
Locked nucleic acid (LNA) is a RNA analog generated by chemically locking the 2′-oxygen and 4′-carbon on ribose with a bridge. The locked structure physically inhibits binding of RNase, resulting in high stability in serum but still leaves the LNA capable of pairing with complementary RNA stands. As a result, LNAs are frequently used to bind complementarily to functional miRNAs for use in fluorescence staining or targeted inhibition (Wahlestedt et al., 2000). While unmodified oligonucleotides can be degraded within 1.5 hours in serum, the half-life of LNA in serum can reach up to 15 hours (Kurreck et al., 2002). LNA-based anti-miR-155 drug (MRG106) administered through intratumoral injection was developed by MiRagen Therapeutics, which is currently undergoing Phase 1 clinical trial for patients with cutaneous T-cell lymphoma (CTCL) of the mycosis fungoides (MF) sub-type (NCT02580552).
Strategies, Design, and Chemistry in Small Interfering RNA Delivery Vehicle Systems for Cancer Therapy
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
The 2′-position is the most common modification site in nucleotides. In 1959, Smith and Dunn isolated 2’-O-methyladenosine from the wheat germ and rat liver [188]. The selective synthesis of this compound using diazomethane and 1,2-dimethoxyethane was described by Robins and coworkers [189]. Because chemical modification can potentially inhibit activity, Rana and coworkers performed a chemical modification analysis for siRNA function [187]. Their results indicated that 2’-OHs are not required for the siRNA activity and that 2′ modification could significantly improve the stability of siRNA and extend their half-life [187]. The 2′-position has been modified with a number of residues including 2’-Omethyl, 2’-O-methoxyethyl, and fluoro (Figure 2.8). Conformational constrained nucleotides such as locked nucleic acid (LNA) were developed by Imanishi and Wengel independently [190,191]. Introduction of LNA bases not only improves the stability of siRNA but can also increase the binding affinity to RNA [186]. Recently, an α-L-tricyclic nucleic acid was developed, which is also highly constrained (Figure 2.8) [192].
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Published in Chad A. Mirkin, Spherical Nucleic Acids, 2020
Lam-Kiu Fong, Ziwei Wang, George C. Schatz, Erik Luijten, Chad A. Mirkina
It has been observed that molecular crowding or excluded-volume effects increase local DNA concentration and as a result stabilize duplex formation [33, 34]. Yet, excluded volume also restricts the degrees of freedom of hybridizing molecules and biases the DNA toward more enthalpically stable conformations. This effect is reminiscent of the stability observed for locked nucleic acid (LNA) hybridization. LNA is a synthetic RNA analog for which the ribose moiety is structurally constrained by a 2′ oxygen to 4′ carbon methylene bridge [39]. Incorporation of LNA bases into DNA oligomers has led to a demonstrated enhancement of the thermodynamic stability of duplexes [40]. This effect is enthalpically dominated, as shown by calorimetry [41] and is thought to result from the conformational restriction of base-stacking and hydrogen-bonding interactions [42, 43].
Advances of engineered extracellular vesicles-based therapeutics strategy
Published in Science and Technology of Advanced Materials, 2022
Hiroaki Komuro, Shakhlo Aminova, Katherine Lauro, Masako Harada
MicroRNAs (miRNAs) are small non-coding RNAs, typically 20–22 nucleotides long. Like siRNAs, they bind to mRNAs through complementary base pairing [281]. This binding leads to either the degradation of the mRNA or inhibition of the mRNA’s translation. miRNAs have roles in almost all biological functions due to their constant presence and regulation of key genes in maintaining homeostasis. Any alterations in certain miRNA levels can promote disease progression, typically seen in cancers. For example, O’Brien et al. noticed miR-379 expression was reduced in breast cancer tissues of patients, and others have reported decreased expression in hepatocellular carcinoma and osteosarcoma tissues [282–285]. They engineered mesenchymal stem cells to secrete miR-379 enriched EVs and noticed their therapeutic potential after administering them into mice [282]. Wang et al., alternatively, noticed low levels of miR-335 in human liver cells [286]. To test if miR-335 can be used against hepatocellular carcinoma progression, they endogenously loaded miR-335 into L×2 cells and isolated the loaded EVs [286]. The researchers tested these EVs in both cancer cell lines and HCC infected mice and found that EV loaded miR-335 inhibited cancer progression and invasion [286]. When naked miRNAs are administered, they are prone to early degradation and are limited by the accessibility of the administration site. There are many clinical studies utilizing miRNAs with liposomal, or locked nucleic acid (LNA) delivery systems, and while none are using EVs yet, clinical trials with siRNAs will pave the path for miRNA in EV therapeutic delivery systems [287]. As EVs are natural carriers of miRNAs, the delivery system has few faults, if any, outside of the difficulties associated with EV production.
PEG-modification on the endo-position of an antisense oligonucleotide increases tumor accumulation via the EPR effect
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Kenji Hagiwara, Kana Kurihara, Masakazu Honma, Junichiro Yamamoto, Fumikazu Shinohara
Locked Nucleic Acid (LNA) antisense oligonucleotide (ASO) targeting the mouse Scarb1 mRNA was chemically synthesized by GeneDesign, Inc. The ASO sequence is as follows: LC^LA^G^T^C^A^T^G^A^C^LT^LT^LC^:Phosphorothioate bond, LX:LNA, LC:LNA 5-Methyl cytosine, A, G, C, T:DNA.