siRNA Conjugate Delivery Systems

Jeong, Ji Hoon; Mok, Hyejung; Oh, Yu‐Kyoung; Park, Tae Gwan

doi:10.1021/bc800278e

Cited by 309 publications

(228 citation statements)

References 83 publications

(123 reference statements)

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“…To address these problems, two strategies have been pursued: development of noncharged and nonbiodegradable siRNA surrogates (10) and, more directly, development of delivery vehicles and strategies that would enable or enhance the entry of siRNA itself. Several siRNA delivery technologies have been reported thus far, including direct covalent conjugation of siRNA to lipids, peptides, or to aptamers; and noncovalent complexation of siRNA with polymers, biopolymers, nanotubes, lipid-based vehicles (e.g., lipopolyplexes, stable nucleic acid lipid nanoparticles), cyclodextrin polymer-based nanoparticles, fusion proteins, membrane translocation-modified magnetic nanoparticles, and antibodyprotamine conjugates (4,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).In 2000, we reported an extensive reverse engineering effort directed at the highly cationic HIV-Tat 9-mer peptide (RKKRRQRRR), showing that its ability to enter cells is related to its arginine content and, more specifically, to the number and array of its guanidinium groups (23). This finding led to the design of oligoarginine and guanidinium-rich peptoid cell penetrating agents and, subsequently, a wide range of designed nonpeptidic agents, more generally and accurately dubbed molecular transporters, differing in backbone structure but uniformly incorporating the key guanidinium head groups (24).…”

mentioning

confidence: 99%

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Geihe

Cooley

Simon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

142

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The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.amphipathic co-oligomers | nanoparticles | oligonucleotide delivery | biodegradable oligomers | organocatalysis R NA interference (RNAi) is an emerging technology that is revolutionizing many strategic approaches to biochemical pathway analysis, drug discovery, and therapy (1-6). As part of the RNAi pathway, small interfering RNAs (siRNAs) induce post-transcriptional, sequence-specific gene silencing utilizing endogenous intracellular machinery to selectively suppress gene expression and, thereby, reduce target protein synthesis (7). The net effect is equivalent to protein inhibition without the use of small molecule inhibitors. The specificity of RNAi also allows one to make inhibitors against previously undruggable targets. Both the ubiquity of the RNAi pathway within the body and the ease with which siRNA can be used to suppress a specific target of interest have made siRNAs a promising class of molecules for the treatment of cancer, viral infections, ocular disorders, and genetic diseases (5). In 2004, the first siRNA-based therapy entered Phase 1 clinical trials (4). Since then, several other RNAi-based therapies have reached clinical evaluation for a number of indications including cancer, viral infections, and genetic skin disorders (5,8,9). Notwithstanding this progress, formidable challenges remain for the application of RNAi technology in basic research and therapy, the most fundamental of which is delivery of siRNA across biological barriers.The siRNAs are double-stranded RNA molecules typically consisting of a 19-23 base-paired region with two 3′ overhanging nucleotides. It is polyanionic, polar, and large (ca. 13 kDa), compared to small molecule therapeutics. These physical properties suppress or prevent its unassisted passage through nonpolar membranes and, thus, its access to the intracellular RNA-induced silencing complex (RISC) components required for target protein knockdown (6). This problem is further exacerbated by siRNA's susceptibility to enzymatic degradation (i.e., RNases) (3). To address these problems, two strategies have been pursued: d...

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mentioning

confidence: 99%

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Geihe

Cooley

Simon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

142

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“…In contrast to other non-viral methods (cationic lipids and polymers, high-pressure injections) the advantages of conjugation include the cell-specificity and the absence of toxic effect [63,146,147,148,149]. The employment of cholesterol-and folate-contaning siRNAs in vivo is less specific, since LDL-and folate-receptors are expressed by different cells [125,150], however, this approach is could be usefully applied when strict cell or tissue selectivity is not required.…”

Section: Bioconjugatesmentioning

confidence: 99%

“…To increase the specificity of uptake by the attachment of the molecules with high binding affinity to surface of the cells of particular organs and tissues 154 .…”

Section: Chol 2'-o-dnp Folatementioning

confidence: 99%

Structure - Functions Relations in Small Interfering RNAs

Petrova¹,

Зенкова²,

Chernolovskaya³

2013

Practical Applications in Biomedical Engineering

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“…14 Both structures have a short in vivo half life. 10,17,21 Poly(ethylene glycol) (PEG) is a well-known, nonimmunogenic, long-circulating polymer. Covalent conjugation of PEG ("PEGylation") has been shown to improve the in vivo pharmacokinetics of protein drugs by reducing immunogenicity and preventing rapid clearance.…”

Section: ■ Introductionmentioning

confidence: 99%

Dicer-Labile PEG Conjugates for siRNA Delivery

et al. 2011

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Poly(ethylene glycol) (PEG) conjugates of Dicer-substrate small interfering RNA (DsiRNA) have been prepared to investigate a new siRNA release strategy. 3′-sense or 5′-antisense thiol-modified, blunt-ended DsiRNAs, inhibiting enhanced green fluorescent protein (eGFP) expression, were covalently conjugated to PEG with varying molecular weights (2, 10, and 20 kg/mol) through a stable thioether bond using a Michael addition reaction. The DsiRNA conjugates with 2 kg/mol PEG (both 3′-sense or 5′-antisense strand conjugated) and the 10 kg/mol PEG conjugated to the 3′-sense strand of DsiRNA were efficiently cleaved by recombinant human Dicer to 21-mer siRNA, as determined by gel electrophoresis. Importantly, 2 and 10 kg/mol PEG conjugated to the 3′-sense strand of DsiRNA showed potent gene silencing activity in human neuroblastoma (SH-EP) cells, stably expressing eGFP, at both the mRNA and protein levels. Moreover, the 10 kg/mol PEG conjugates of the 3′-sense strand of DsiRNA were less immunogenic when compared with the unmodified DsiRNA, determined via an immune stimulation assay on human peripheral blood mononuclear cells.

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siRNA Conjugate Delivery Systems

Cited by 309 publications

References 83 publications

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Structure - Functions Relations in Small Interfering RNAs

Dicer-Labile PEG Conjugates for siRNA Delivery

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