RNA interference technology with emphasis on delivery vehicles—prospects and limitations

Prabha, Shashi; Vyas, R B; Gupta, Nidhi; Ahmed, Bahar; Chandra, Ramesh; Nimesh, Surendra

doi:10.3109/21691401.2015.1058808

Cited by 8 publications

(8 citation statements)

References 86 publications

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“…Covalent coupling is commonly used for conjugation of drugs, fluorescent labels, antibody fragments and targeting moieties to a peptide sequence [28]. Non-covalent complexes are most widely used for delivery of oligonucleotides such as splice correcting oligonucleotides (SCO), siRNA and plasmids [29][30][31]. The main drawback of non-covalent interaction is its weak attraction which leads to uncontrolled release of cargo before reaching its target in some cases.…”

Section: Discussionmentioning

confidence: 99%

Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides

Soleymani-Goloujeh

Nokhodchi

Niazi

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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In conclusion, it was shown that cytotoxicity of modified peptides which were physically linked with MTX, considerably higher than both physically loaded unmodified peptides and chemically conjugated peptides with MTX. Also, cell internalization was reduced after peptide end-protection. These findings confirmed the effectiveness of N- and C-terminal modifications on cell viability and CPPs internalization.

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Section: Discussionmentioning

confidence: 99%

Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides

Soleymani-Goloujeh

Nokhodchi

Niazi

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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“…Although cellular penetration is important, gene therapeutics must also reach the appropriate cell to be effective 18 , 19 , 32 – 34 . Here we present a solution to these problems that uses NPs containing a targeting peptide specific for activated macrophages and a fusogenic liposomal coating (F-pSi).…”

Section: Introductionmentioning

confidence: 99%

Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus

et al. 2018

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The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system’s response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia.

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“…Lack of safe and efficient delivery of siRNA to target tissues or organs also constitutes a serious obstacle to using this technology for a host of diseases. 29,32,69,70 Because of their high molecular weight ($14 kDa) and highly polyanionic nature, naked DsiRNAs, like siRNAs, do not freely diffuse across cell membrane. Indeed, naked RNA usually gives poor silencing rates at low doses and become toxic at high doses.…”

Section: Discussionmentioning

confidence: 99%

Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

et al. 2016

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BackgroundAccumulating evidence suggests that the C-C chemokine ligand 2 (CCL2, or monocyte chemoattractant protein 1) acts as a neuromodulator in the central nervous system through its binding to the C-C chemokine receptor 2 (CCR2). Notably, it is well established that the CCL2/CCR2 axis plays a key role in neuron-glia communication as well as in spinal nociceptive transmission. Gene silencing through RNA interference has recently emerged as a promising avenue in research and drug development, including therapeutic management of chronic pain. In the present study, we used 27-mer Dicer-substrate small interfering RNA (DsiRNA) targeting CCR2 and assessed their ability to reverse the nociceptive behaviors induced by spinal CCL2 injection or following intraplantar injection of complete Freund’s adjuvant.ResultsTo this end, we first developed high-potency DsiRNAs designed to target different sequences distributed across the rat CCR2 (rCCR2) messenger RNA. For optimization, methyl groups were added to the two most potent DsiRNA candidates (Evader and M7 2′-O-methyl modified duplexes) in order to improve in vivo duplex stability and to reduce potential immunostimulatory activity. Our results demonstrated that all modified candidates formulated with the cell-penetrating peptide reagent Transductin showed strong RNAi activity following intrathecal delivery, exhibiting >50% rCCR2 knockdown in lumbar dorsal root ganglia. Accordingly, we found that these DsiRNA duplexes were able to reduce spinal microglia activation and were effective at blocking CCL2-induced mechanical hypersensitivity. Along with similar reductions of rCCR2 messenger RNA, both sequences and methylation patterns were similarly effective in inhibiting the CCL2 nociceptive action for the whole seven days testing period, compared to mismatch DsiRNA. DsiRNAs against CCR2 also reversed the hypernociceptive responses observed in the complete Freund’s adjuvant-induced inflammatory chronic pain model.ConclusionAltogether, these results validate CCR2 as a an appropriate molecular target for pain control and demonstrate that RNAi-based gene therapy represent an highly specific alternative to classical pharmacological approaches to treat central pathologies such as chronic pain.

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RNA interference technology with emphasis on delivery vehicles—prospects and limitations

Abstract: With the current challenges, there is a need for collaborative work allowing for the successful development of nanoparticle/siRNA complexes as health-promoting biotherapeutics.

Cited by 8 publications

References 86 publications

Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides

Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides

Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus

Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

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