siRNA-cell-penetrating peptides complexes as a combinatorial therapy against chronic myeloid leukemia using BV173 cell line as model

Freire, João Miguel; Figueiredo, Inês; Valle, Javier; Veiga, Ana Salomé; Andreu, David; Enguita, Francisco J.; Castanho, Miguel A. R. B.

doi:10.1016/j.jconrel.2016.11.027

Cited by 31 publications

(23 citation statements)

References 59 publications

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“…Various, creative strategies have been employed to surmount these barriers. Electrostatic charge interaction between cationic CPPs and negatively charged siRNAs have produced self-assembly of CPPs and siRNA into nanoparticles [96][97][98][99]. Escape from endosomal compartments has been achieved by acylation [99], stearylation [100] or histidine modification [101] of the N-terminus of CPPs.…”

Section: Small Interfering Rnamentioning

confidence: 99%

Cell Penetrating Peptides, Novel Vectors for Gene Therapy

2020

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Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids.

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Section: Small Interfering Rnamentioning

confidence: 99%

Cell Penetrating Peptides, Novel Vectors for Gene Therapy

2020

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“…Via covalent linkage, CPPs were shown to be capable of delivering a wide variety of cargos into primary cells and most tissues in preclinical models 17, 19. Ample evidence also demonstrated that even through electrostatic condensation of the polyanionic DNA or siRNA with the polycationic CPP was also capable of inducing reasonable intracellular uptake of these drugs via the mechanism of macropinocytosis 18-20; albeit that CPP-mediated cell translocation of such non-covalently linked complexes were far less effective than the covalent conjugates 21. Hence, the most ideal means in realizing the therapeutic potential of the siRNA drugs is by formulating a soluble, monomeric CPP-siRNA conjugate through a covalent yet cytosol-cleavable linkage, so that CPP can mediate a potent intracellular delivery of siRNA via its unique endocytosis- independent pathway, but is then detached from the drug to allow siRNA remain in the cytosol, executing its gene-silencing therapeutic functions by means of the RISC system.…”

Section: Introductionmentioning

confidence: 99%

High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA

Liu

Gong

et al. 2017

Theranostics

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Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice. Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications. With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides. However, construction of such a chemical conjugate has been referred by scientists in this field as the “Holy Grail” challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds. Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates. Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities. This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation. To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.

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“…It is possible that attachment of 9R to TP enhances the binding ability and stabilizes the cargo. CPPs showed lower toxicity as an siRNA delivery tool compared with viral vectors, but results published by Freire et al suggest that CPPs themselves perturb cellular pathways 52. Further investigation needs to be designed to test toxicity of T9(dR) both in vitro and in vivo to assure a safe siRNA delivery platform in medical application.…”

Section: Discussionmentioning

confidence: 99%

<p>Transportan-derived cell-penetrating peptide delivers siRNA to inhibit replication of influenza virus in vivo</p>

Zhang¹,

Ren²,

Liu³

et al. 2019

DDDT

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Introduction In this study, we report on the development of an effective delivery system for siRNAs; a novel cell-penetrating peptide (CPP), T9(dR), obtained from transportan (TP), was used for in vivo and in vitro testing. Methods In this study, toxicity of T9(dR) and TP and efficient delivery of siRNA were tested in 293T, MDCK, RAW, and A549 cells. Furthermore, T9(dR)- and TP-delivered siRNAs against nucleoprotein (NP) gene segment of influenza virus (siNP) were studied in both cell lines and mice. Results Gel retardation showed that T9(dR) effectively condensed siRNA into nanoparticles sized between 350 and 550 nm when the mole ratio of T9(dR) to siRNA was ≥4:1. In vitro studies demonstrated that T9(dR) successfully delivered siRNA with low cellular toxicity into several cell lines. It was also observed that T9(dR)-delivered siRNAs inhibited replication of influenza virus more efficiently as compared to that delivered by TP into the MDCK and A549 cells. It was also noticed that when given a combined tail vein injection of siNP and T9(dR) or TP, all mice in the 50 nmol siNP group infected with PR8 influenza virus survived and showed weight recovery at 2 weeks post-infection. Conclusion This study indicates that T9(dR) is a promising siRNA delivery tool with potential application for nucleotide drug delivery.

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siRNA-cell-penetrating peptides complexes as a combinatorial therapy against chronic myeloid leukemia using BV173 cell line as model

Cited by 31 publications

References 59 publications

Cell Penetrating Peptides, Novel Vectors for Gene Therapy

Cell Penetrating Peptides, Novel Vectors for Gene Therapy

High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA

<p>Transportan-derived cell-penetrating peptide delivers siRNA to inhibit replication of influenza virus in vivo</p>

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