Design, synthesis and evaluation of novel, branched trident small interfering RNA nanostructures for sequence-specific RNAi activity

Chandela, Akash; Ueno, Yoshihito

doi:10.1039/c9ra08071f

Cited by 4 publications

(5 citation statements)

References 34 publications

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“…As shown in Figure 3, bands of full‐length strands of both DNA dendrons could be observed after 12 h of incubation, while almost all the linear ODNs were found to have degraded within 8 h of incubation, suggesting that covalent branching of ODNs could enhance their nuclease resistance. A similar enhancement was observed in branched siRNA; [23c] coating DNA nanostructures with DNA dendrons was reported to enhance the stability of the nanostructures, attributed to steric hindrance [22j] . This enhancement of nuclease resistance by the formation of covalent DNA dendrons was also found to be ascribed to the steric blocking of nuclease by multiple DNA strands.…”

Section: Resultssupporting

confidence: 55%

“…The phosphoramidite of the branching trebler unit was synthesized using pentaerythritol 1 based on Scheme 1. Its synthetic route was modified from the reported one to avoid highly flammable lithium aluminum hydride used in the previous study [22a,23c] . One of the hydroxyl groups of compound 1 was protected by the tert ‐butyldimethylsilyl (TBDMS) group to afford compound 2 , and the other hydroxyl groups were allowed to react with allyl bromide in the presence of sodium hydride to provide the elongated compound 3 .…”

Section: Resultsmentioning

confidence: 99%

“…This dendritic scaffold is also effective for therapeutics based on the multiple ligand system [24] . Therefore, covalent DNA dendrons are promising therapeutic molecules for oligonucleotide therapeutics; however, there are only a few studies on their therapeutic potential [22d,e,g–i,k,23b,c] compared with non‐covalent, self‐assembly based DNA dendrimers [16,25] …”

Section: Introductionmentioning

confidence: 99%

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Enhanced Immunostimulatory Activity of Covalent DNA Dendrons

et al. 2021

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The present study focused on the design and synthesis of covalent DNA dendrons bearing multivalent cytosine‐phosphate‐guanine oligodeoxynucleotides (CpG ODNs) that can stimulate the immune system through the activation of TLR9. These dendrons were synthesized using branching trebler phosphoramidite containing three identical protecting groups that enabled the simultaneous synthesis of multiple strands on a single molecule. Compared with linear ODNs, covalent DNA dendrons were found to be more resistant to nuclease degradation and were more efficiently taken up by macrophage‐like RAW264.7 cells. Cellular uptake was suggested to be mediated by macrophage scavenger receptors. The covalent DNA dendrons composed of multivalent immunostimulatory branches enhanced the secretion of proinflammatory cytokines TNF‐α and IL‐6 from RAW264.7 cells, and 9‐branched DNA dendrons showed the highest enhancement. Given their enhanced efficacy, we expect covalent DNA dendrons to be useful structures of oligonucleotide medicines.

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced Immunostimulatory Activity of Covalent DNA Dendrons

et al. 2021

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“…Further, analyzing the size of particles in prepared solutions (Table 2), in the case of AuNP13 analogues, two peaks were observed which, judging by the size, can be attributed to free nanoparticles 10 and free siRNA. 35,36 This indicates that the AuNP13 analogues practically did not form complexes with the nucleic acid. Interestingly, the diameter of free nanoparticles increased with concentration, which may point to the formation of agglomerates (especially in the case of AuNP13a).…”

Section: ■ Resultsmentioning

confidence: 97%

PEGylation of Dendronized Gold Nanoparticles Affects Their Interaction with Thrombin and siRNA

et al. 2021

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The use of nonviral carriers based on nanomaterials is a promising strategy for modern gene therapy aimed at protecting the genetic material against degradation and enabling its efficient cellular uptake. To improve the effectiveness of nanocarriers in vivo, they are often modified with poly(ethylene glycol) (PEG) to reduce their toxicity, limit nonspecific binding by proteins in the bloodstream, and extend blood half-life. Thus, the selection of an appropriate degree of surface PEGylation is crucial to preserve the interaction of nanoparticles with the genetic material and to ensure its efficient transport to the site of action. Our research focuses on the use of innovative gold nanoparticles (AuNPs) coated with cationic carbosilane dendrons as carriers of siRNA. In this study, using dynamic light scattering and zeta potential measurements, circular dichroism, and gel electrophoresis, we investigated dendronized AuNPs modified to varying degrees with PEG in terms of their interactions with siRNA and thrombin to select the most promising PEGylated carrier for further research.

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“…Another option for the design of branched siRNAs is the connection of monomeric siRNAs through a hexaethylene linker [ 87 ]. These molecules are stable in serum and have no off-target effects.…”

Section: Multimeric Sirnasmentioning

confidence: 99%

Structural Modifications of siRNA Improve Its Performance In Vivo

Chernikov

Ponomareva

Chernolovskaya

2023

IJMS

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The use of small interfering RNA (siRNA) in the clinic gives a wide range of possibilities for the treatment of previously incurable diseases. However, the main limitation for biomedical applications is their delivery to target cells and organs. Currently, delivery of siRNA to liver cells is a solved problem due to the bioconjugation of siRNA with N-acetylgalactosamine; other organs remain challenging for siRNA delivery to them. Despite the important role of the ligand in the composition of the bioconjugate, the structure and molecular weight of siRNA also play an important role in the delivery of siRNA. The basic principle is that siRNAs with smaller molecular weights are more efficient at entering cells, whereas siRNAs with larger molecular weights have advantages at the organism level. Here we review the relationships between siRNA structure and its biodistribution and activity to find new strategies for improving siRNA performance.

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Design, synthesis and evaluation of novel, branched trident small interfering RNA nanostructures for sequence-specific RNAi activity

Abstract: Branched small interfering RNAs (siRNAs) are potential candidates for on-target gene silencing with enhanced serum stability. Their physical characterization also presents them as a prospective drug for systemic delivery.

Cited by 4 publications

References 34 publications

Enhanced Immunostimulatory Activity of Covalent DNA Dendrons

Enhanced Immunostimulatory Activity of Covalent DNA Dendrons

PEGylation of Dendronized Gold Nanoparticles Affects Their Interaction with Thrombin and siRNA

Structural Modifications of siRNA Improve Its Performance In Vivo

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