Polymeric <scp>siRNA</scp> delivery vectors: knocking down cancers with polymeric‐based gene delivery systems

Ardana, Aditya; Whittaker, Andrew K.; McMillan, Nigel A.J.; Thurecht, Kristofer J.

doi:10.1002/jctb.4508

Cited by 15 publications

(10 citation statements)

References 104 publications

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“…In the last years, many siRNA delivery strategies based on cationic polymers have been proposed. Good results were obtained with PEI, PLL and PAMAM [37][38][39][40][41][42]. In some cases, lipophilic moieties were introduced to increase efficiency by facilitating crossing of the cell membranes.…”

Section: Figurementioning

confidence: 99%

The AGMA1 polyamidoamine mediates the efficient delivery of siRNA

Cavalli

Primo

Sessa

et al. 2017

Journal of Drug Targeting

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AGMA1, a prevailingly cationic, guanidine-bearing, linear, amphoteric polyamidoamine is an effective siRNA condensing agent. Here two AGMA1 samples of different molecular weight, i.e. AGMA1-5 and AGMA1-10 were evaluated as siRNA condensing agents and transfection promoters. AGMA1-10 formed stable polyplexes with a size lower than 50 nm and positive zeta potential. AGMA1-5 polyplexes were larger, about 100 nm in size. AGMA1-10 polyplexes, but not AGMA1-5 proved to be an effective intracellular siRNA carrier, able to trigger gene silencing in Hela and PC3 cell lines without eliciting cytotoxic effects. AGMA1-10 knocked down AKT-1 expression upon transfection with an AKT-1 specific siRNA. The polyplex entry mechanism was investigated and was mediated by macropinocytosis. In conclusion, AGMA1 has potential as an efficient, non-toxic tool for the intracellular delivery of siRNA and warrants further investigation.

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Section: Figurementioning

confidence: 99%

The AGMA1 polyamidoamine mediates the efficient delivery of siRNA

Cavalli

Primo

Sessa

et al. 2017

Journal of Drug Targeting

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“…Examples of delivery carriers are liposomes, 19 polymers, 3 magnetic nanoparticles, 20 protein particles, dendrimers, inorganic materials, and viral particles. [21][22][23][24] In addition, instead of using plain siRNAs, RNA nanostructures have been studied and have shown potential for controlled and efficient delivery of RNAi inducers. 25 In our previous studies, we synthesized bolaamphiphiles (bolas) with positively charged head groups that have relatively low toxicity and high stability in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Cationic Bolaamphiphile Vesicles for siRNA Delivery into Tumors and Brain

Kim

Viard

Afonin

et al. 2020

Molecular Therapy - Nucleic Acids

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Small interfering RNAs (siRNAs) are potential therapeutic substances due to their gene silencing capability as exemplified by the recent approval by the US Food and Drug Administration (FDA) of the first siRNA therapeutic agent (patisiran). However, the delivery of naked siRNAs is challenging because of their short plasma half-lives and poor cell penetrability. In this study, we used vesicles made from bolaamphiphiles (bolas), GLH-19 and GLH-20, to investigate their ability to protect siRNA from degradation by nucleases while delivering it to target cells, including cells in the brain. Based on computational and experimental studies, we found that GLH-19 vesicles have better delivery characteristics than do GLH-20 vesicles in terms of stability, binding affinity, protection against nucleases, and transfection efficiency, while GLH-20 vesicles contribute to efficient release of the delivered siRNAs, which become available for silencing. Our studies with vesicles made from a mixture of the two bolas show that they were able to deliver siRNAs into cultured cancer cells, into a flank tumor and into the brain. The vesicles penetrate cell membranes and the bloodbrain barrier (BBB) by endocytosis and transcytosis, respectively, mainly through the caveolae-dependent pathway. These results suggest that GLH-19 strengthens vesicle stability, provides protection against nucleases, and enhances transfection efficiency, while GLH-20 makes the siRNA available for gene silencing.

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“…The latter strategy, where polymer-nucleic acid complexes (polyplexes) are generated via ionic interactions between cationic polymers and negatively charged RNA has been more frequently investigated. Whilst nitrogen-containing cationic polymers such as N,N-dimethylaminoethyl methacrylate (DMAEMA), polyethylenimine (PEI), poly(l-lysine) and others are commonly used 36,37 , polymers incorporating phosphonium salt functionalities have recently started to gain interest as novel materials with a range of properties complementing existing nitrogen-based systems [38][39][40][41][42][43][44] . Phosphonium-containing polymers have been engineered with reduced cytotoxicity and efficient binding of oligonucleotides, at least in part due to the different ionic radius and charge distribution of quaternary phosphonium salts compared to their corresponding ammonium counterparts [38][39][40] .…”

Section: Introductionmentioning

confidence: 99%

Phosphonium Polymethacrylates for Short Interfering RNA Delivery: Effect of Polymer and RNA Structural Parameters on Polyplex Assembly and Gene Knockdown

et al. 2015

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(2015) Phosphonium polymethacrylates for siRNA delivery: effect of polymer and RNA structural parameters on polyplex assembly and gene knockdown. Biomacromolecules, 16 (11). pp. 3480-3490. ISSN 1525-7797 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/35894/1/Phosphonium%20Polymethacrylates%20for %20Short%20Interfering%20RNA%20Delivery%20-%20%20Effect%20of%20Polymer %20and%20RNA%20Structural%20Parameters%20on%20Polyplex%20Assembly%20and %20Gene%20Knockdown%20-%20AAM.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. ABSTRACT: Synthetic polymers containing quaternary phosphonium salts are an emerging class of materials for the delivery of oligo/polynucleotides. In this work, cationic phosphonium saltcontaining polymethacrylates -and their corresponding ammonium analogues-were synthesized by RAFT polymerization. Both the nature of the charged heteroatom (N vs. P) and the length of the spacer separating the cationic units along the polymer backbone (oxyethylene vs. trioxyethylene) were systematically varied. Polymers efficiently bound siRNA at N + /P -or P + /Pratios of 2 and above. At a 20:1 ratio, small polyplexes (Rh: 4-15 nm) suitable for cellular uptake were formed that displayed low cytotoxicity. Whilst siRNA polyplexes from both ammonium and phosphonium polymers were efficiently internalised by GFP-expressing 3T3 cells, no knockdown of GFP expression was observed. However, 65% Survivin gene knockdown was observed when short interfering RNA (siRNA) was replaced with novel, multimerised long interfering liRNA 2 (liRNA) in HeLa cells, demonstrating the importance of RNA macromolecular architecture on RNA-mediated gene silencing.

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Polymeric siRNA delivery vectors: knocking down cancers with polymeric‐based gene delivery systems

Cited by 15 publications

References 104 publications

The AGMA1 polyamidoamine mediates the efficient delivery of siRNA

The AGMA1 polyamidoamine mediates the efficient delivery of siRNA

Characterization of Cationic Bolaamphiphile Vesicles for siRNA Delivery into Tumors and Brain

Phosphonium Polymethacrylates for Short Interfering RNA Delivery: Effect of Polymer and RNA Structural Parameters on Polyplex Assembly and Gene Knockdown

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