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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
The discovery that dsRNA can trigger catalytic degradation of messenger RNA (mRNA) has inspired more than two decades of research aimed at understanding and harnessing this mechanism. Because well-designed RNA interference (RNAi) therapeutics can potently and specifically suppress translation of any gene, including intracellular targets traditionally considered “undruggable,” they have been heavily studied as a potential new class of pharmaceutics that can modulate drug targets that are inaccessible by conventional small-molecule inhibitors and antibody drugs. In particular, synthetic, double-stranded small-interfering RNA (siRNA) has emerged as a leading candidate for the development of gene silencing therapeutics [1,2]. siRNA is potentially advantageous in comparison to other RNAi approaches because it can directly load into the RNA-induced silencing complex (RISC) machinery, simplifying dosing control and circumventing the requirement for delivery into the nucleus (e.g., as required with shRNA-encoding vectors) [3,4]. However, emergence of clinically approved siRNA therapies has remained slow, with the primary challenge being the formidable anatomical and physiological barriers that must be overcome to deliver siRNA to its intracellular site of action in target cell types [5].
RNAi as New Class of Nanomedicines
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Monika Dominska, Derek M. Dykxhoorn
RNA interference (RNAi)-based gene-silencing technologies provide a novel approach for the treatment of a variety of diseases through the sequence-specific silencing of gene expression. The application of small interfering RNA (siRNA) as potential therapeutic agents requires the development of clinically feasible delivery strategies that enhance their pharmacological properties. To be effective, siRNAs must be delivered to and taken up by specific target cells and tissues, enter the cytoplasm, and associate with the RNA-induced silencing complex (RISC) to guide the sequence-specific cleavage of appropriate messenger RNA (mRNA). This chapter will focus on recent progress made in the development of safe and effective therapeutic strategies for the siRNA-based silencing of gene expression.
Application of Bioresponsive Polymers in Gene Delivery
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Tamgue Serges William, Drashti Pathak, Deepa H. Patel
A different system of delivery is available and involves the applications of non-viral plasmid (pDNA) expression vectors; small interfering RNA (siRNA); single-stranded antisense oligodeoxynucleotides (ODNs) or an immune system stimulating nucleic acid. An ideal gene therapy delivery system would be injectable, targetable to specific sites in vivo, regulatable, and able to maintain long-term gene expression, and be nonimmunogenic. The difficulty in this area would be to design the perfect vector integrating all the parameters required for the efficient expression of the gene. The particles containing DNA must successively process in three major steps (1) to attach with cells, (2) enter the cytoplasm of the cell, by direct fusion with the plasma membrane, either after rupture of intracellular vesicles (endosomes, lysosomes), (3) allow the entry of DNA into cell nucleus [1].
Intracellular controlled release prolongs the time period of siRNA-based gene suppression
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Kazuki Chujo, Jun-ichiro Jo, Yasuhiko Tabata
RNA interference (RNAi) is a gene silencing process by inhibiting target messenger RNA (mRNA) in the sequence-specific manner in the cell cytoplasm. The RNAi was initially discovered by Fire et al. in 1998 [1]. Small interfering RNA (siRNA) is a synthetic double-stranded RNA (dsRNA) of 21–23 base pairs. SiRNA binds to the RNA-induced silencing complex (RISC) in the cell cytoplasm, and then recognizes and cleaves the target mRNA [2, 3]. This RNAi is useful for in the research field of basic cell biology and has extensively utilized to investigate the mechanism of cell functions. In addition, the technology of specific gene suppression is also a promising tool to regulate the cell functions, which plays an important role in regenerative medicine. The regenerative medicine is one of the research fields to control the cell functions aiming at cell-based therapy. However, generally siRNA is not always internalized into cells in the native state. The siRNA-induced suppression of gene expression is not achieved efficiently. As one trial to tackle the issue, it is necessary to develop the vectors to deliver siRNA to the interior of cells. There are some problems to be improved, such as the low efficiency of cellular internalization and the short time period of gene expression suppression [4]. Several viral [5–7] and non-viral vectors [8–10] have been investigated to improve the efficacy of gene expression. In addition, for the viral vectors have issues to be resolved, such as the immunogenicity and cytotoxicity. On the other hand, as the non-viral vectors, cationic liposomes [11–13], micelles [14, 15], nanospheres [16, 17] and gold nanospheres [18, 19] have been extensively investigated. However, the transfection efficiency is low compared with that of viral vectors and the time period of gene expression suppression is short.
‘Borono-lectin’ based engineering as a versatile platform for biomedical applications
Published in Science and Technology of Advanced Materials, 2018
Akira Matsumoto, Yuji Miyahara
There is a growing interest in the delivery of small interfering RNA (siRNA) for its ability of gene silencing in a highly sequence-specific fashion [34,35]. One major approach is a formulation into polyion complex (PIC) micelles that instantly form in an aqueous environment, through electrostatic interactions between anionic siRNA and cationic polymers [36]. The greatest challenge is optimally stabilizing the PIC-micelle; while in the bloodstream it must be robust enough to protect siRNA from the endogenous RNase attack, however, once reaching the site of intracellular targets it is required to adversely destabilize so to release siRNA. To meet these criteria, many attempts have been made, a majority of which focus on either one or combinations of the following three methodologies, namely, covalent conjugation of siRNA to the homing polymer [37–41], introduction of hydrophobic moieties to reinforce the core-aggregate [42–44] and cross-linking the core aggregate by the disulfide bridging [45,46]. However, these combinatorial approaches inevitably yield a complexity in structure and method of preparation. We have demonstrated that BA-ribose interaction, which has been long-studied as ligand chemistry in chromatography, indeed provides a sophisticated solution (Figure 1). Our strategy capitalizes solely on the phenylboronic acid (PBA) functionality, which incorporates all the aforementioned three modes of stabilization effects (Figure 5) [47]. Our platform cationic polymer was poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLys), the lysine residues of which were functionalized with 3-fluoro-4-carboxyphenylboronic acid (FPBA) to graded degrees. In the first stabilization mode, the polymer pendent PBA can serve as group for chemical conjugation with ribose of siRNA. Then, upon electrostatic condensation to form the PIC-micelle, intermolecular cross-links prevail due to bis-bidentate ribose arrangement at each 3′ end of the double-stranded siRNA thereby further stabilizing the complex (2nd mode). Furthermore, PBA is unique in that it undergoes a dramatic inversion in the state of hydrophobicity depending on the degree of acid disassociation, which is sensitive to the ribose or other competing moieties in the milieu, providing an additional (3rd) mode of reversible stabilization.