Block ionomer complexes consisting of siRNA and aRAFT-synthesized hydrophilic-block-cationic copolymers II: the influence of cationic block charge density on gene suppression

Holley, Andrew C.; Munn, Gabrielle A.; Flynt, Alex S.; McCormick, Charles L.

doi:10.1039/c6py01048b

Cited by 10 publications

(20 citation statements)

References 36 publications

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“…23,24 Formation of IPECs confers enhanced RNA stability, providing protection from RNase-mediated degradation. 33−35 pGPMA is chemically similar to CPPs, which can traverse biological membranes and enter cells through both endocytotic and nonendocytotic pathways, 30 and we have previously shown similar behavior for pGPMA. 25 It has been demonstrated that pGPMA has a modest capacity to deliver plasmid DNAs to nuclei, though toxicity was observe in one cell line.…”

Section: Resultsmentioning

confidence: 84%

Guanidinium-Functionalized Interpolyelectrolyte Complexes Enabling RNAi in Resistant Insect Pests

2018

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RNAi-based technologies are ideal for pest control as they can provide species specificity and spare nontarget organisms. However, in some pests biological barriers prevent use of RNAi, and therefore broad application. In this study we tested the ability of a synthetic cationic polymer, poly-[N-(3-guanidinopropyl)methacrylamide] (pGPMA), that mimics arginine-rich cell penetrating peptides to trigger RNAi in an insensitive animal—Spodoptera frugiperda. Polymer–dsRNA interpolyelectrolyte complexes (IPECs) were found to be efficiently taken up by cells, and to drive highly efficient gene knockdown. These IPECs could also trigger target gene knockdown and moderate larval mortality when fed to S. frugiperda larvae. This effect was sequence specific, which is consistent with the low toxicity we found to be associated with this polymer. A method for oral delivery of dsRNA is critical to development of RNAi-based insecticides. Thus, this technology has the potential to make RNAi-based pest control useful for targeting numerous species and facilitate use of RNAi in pest management practices.

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Section: Resultsmentioning

confidence: 84%

Guanidinium-Functionalized Interpolyelectrolyte Complexes Enabling RNAi in Resistant Insect Pests

2018

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“…The dsRNA used in our work is significantly longer than the siRNA often used in studies concerned with therapeutic applications. 30 , 31 , 39 , 44 On that basis, we decided to explore higher degrees of polymerization (DP) for the charged block than that used in the literature for siRNA. Unpublished data from our research group subsequently indicated that a PQDMAEMA DP of 110 was a sufficient length for complexation with the 222 bp dsRNA.…”

Section: Resultsmentioning

confidence: 99%

“…However, cationic homopolymers can exhibit high levels of cytotoxicity, and the polyplexes they form with DNA/RNA can be unstable, with the likeliness of electroneutralization upon complexation with DNA/RNA leading to increased aggregation. 6 , 20 − 22 , 24 − 26 Thus, tailored polymer architectures including branched, 16 , 27 , 28 dendritic, 29 or block copolymers 30 − 33 have recently been evaluated for improving the stabilization of polyplexes for the protection and targeted release of genetic material.…”

Section: Introductionmentioning

confidence: 99%

Protection of Double-Stranded RNA via Complexation with Double Hydrophilic Block Copolymers: Influence of Neutral Block Length in Biologically Relevant Environments

et al. 2022

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Interaction between the anionic phosphodiester backbone of DNA/RNA and polycations can be exploited as a means of delivering genetic material for therapeutic and agrochemical applications. In this work, quaternized poly(2-(dimethylamino)ethyl methacrylate)- block -poly( N , N -dimethylacrylamide) (PQDMAEMA- b -PDMA m ) double hydrophilic block copolymers (DHBCs) were synthesized via reversible addition–fragmentation chain-transfer (RAFT) polymerization as nonviral delivery vehicles for double-stranded RNA. The assembly of DHBCs and dsRNA forms distinct polyplexes that were thoroughly characterized to establish a relationship between the length of the uncharged poly( N,N -dimethylacrylamide) (PDMA) block and the polyplex size, complexation efficiency, and colloidal stability. Dynamic light scattering reveals the formation of smaller polyplexes with increasing PDMA lengths, while gel electrophoresis confirms that these polyplexes require higher N/P ratio for full complexation. DHBC polyplexes exhibit enhanced stability in low ionic strength environments in comparison to homopolymer-based polyplexes. In vitro enzymatic degradation assays demonstrate that both homopolymer and DHBC polymers efficiently protect dsRNA from degradation by RNase A enzyme.

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“…McCormick and co-workers have studied fully hydrophilic guanidinium-rich methacrylamide copolymers for antimicrobial activity, cell-penetration and cell transfection. [24][25][26] In another example, Koschek and co-workers used RAFT polymerisation to prepare a small library of Arginine-containing polymer conjugates and studied the effect of charge and charge distribution on cellular uptake. 27 Among the various factors which can affect the cellular uptake of polymers, hydrophobicity has been found to play a particularly important role.…”

Section: Introductionmentioning

confidence: 99%

Investigating Cell Uptake of Guanidinium-Rich RAFT Polymers: Impact of Comonomer and Monomer Distribution

Martin¹,

Peltier²,

Kuroki³

et al. 2018

Biomacromolecules

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A range of well-defined guanidinium-rich linear polymers with demonstrable efficiency for cellular internalization were developed. A protected guanidinium-functional acrylamide monomer (di-Boc-guanidinium ethyl acrylamide, GEA) was synthesized and then polymerized via RAFT polymerization to yield well-defined homopolymers, which were then deprotected and functionalized with a fluorescein dye to observe and quantify their cellular uptake. The cellular uptake of these homopolymers was first compared to analogous polyarginines, which are commonly used in modern drug delivery. Following this, a range of well-defined guanidinium-rich copolymers were prepared in which the monomer distribution was varied using a convenient one-pot sequential RAFT polymerization approach. Systematic quantification of the cell uptake of these compounds, supported by fluorescent confocal microscopy data, revealed that while the overall hydrophobicity of the resulting copolymers has a direct impact on the amount of copolymer taken up by cells, the distribution of monomers has an influence on both the extent of uptake and the relative extent to which each route of internalization (endocytosis vs direct translocation) is exploited.

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Block ionomer complexes consisting of siRNA and aRAFT-synthesized hydrophilic-block-cationic copolymers II: the influence of cationic block charge density on gene suppression

Cited by 10 publications

References 36 publications

Guanidinium-Functionalized Interpolyelectrolyte Complexes Enabling RNAi in Resistant Insect Pests

Guanidinium-Functionalized Interpolyelectrolyte Complexes Enabling RNAi in Resistant Insect Pests

Protection of Double-Stranded RNA via Complexation with Double Hydrophilic Block Copolymers: Influence of Neutral Block Length in Biologically Relevant Environments

Investigating Cell Uptake of Guanidinium-Rich RAFT Polymers: Impact of Comonomer and Monomer Distribution

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