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Biomacromolecules. 2015 Nov 9;16(11):3480-90. doi: 10.1021/acs.biomac.5b00898. Epub 2015 Oct 7.

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

Author information

1
School of Pharmacy, University of Nottingham , Boots Science Building, University Park, Nottingham NG7 2RD, U.K.
2
Global Research Laboratory for RNAi Medicine, Department of Chemistry, Sungkyunkwan University , Suwon 440-746, Republic of Korea.
3
Department of Chemistry, University of Sheffield , Dainton Building, Sheffield S3 7HF, U.K.
4
Pharmaceutical Development, Astrazeneca UK Ltd. , Alderley Park, Macclesfield SK10 2NA, U.K.

Abstract

Synthetic polymers containing quaternary phosphonium salts are an emerging class of materials for the delivery of oligo/polynucleotides. In this work, cationic phosphonium salt-containing polymethacrylates and their corresponding ammonium analogues were synthesized by reversible addition-fragmentation chain transfer 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 short interfering RNA (siRNA) at N(+)/P(-) or P(+)/P(-) ratios 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. While siRNA polyplexes from both ammonium and phosphonium polymers were efficiently internalized by green fluorescent protein (GFP)-expressing 3T3 cells, no knockdown of GFP expression was observed. However, 65% Survivin gene knockdown was observed when siRNA was replaced with novel, multimerized long interfering RNA in HeLa cells, demonstrating the importance of RNA macromolecular architecture on RNA-mediated gene silencing.

PMID:
26397811
DOI:
10.1021/acs.biomac.5b00898
[Indexed for MEDLINE]

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