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Phosphonium Polymethacrylates for Short Interfering RNA Delivery: Effect of Polymer and RNA Structural Parameters on Polyplex Assembly and Gene Knockdown
journal contribution
posted on 2015-11-09, 00:00 authored by Vanessa Loczenski Rose, Saif Shubber, S. Sajeesh, Sebastian G. Spain, Sanyogitta Puri, Stephanie Allen, Dong-Ki Lee, G. Sebastiaan Winkler, Giuseppe MantovaniSynthetic 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.
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GFP expressionPolyplex AssemblyratioPhosphonium PolymethacrylatesPolymerquaternary phosphonium saltsGene KnockdownSynthetic polymersammonium analoguesN vs PHeLa cellsgeneoxyethylene vs trioxyethylenesiRNA polyplexesknockdownRNA Structural Parametersphosphonium polymerspolymer backbonecationic unitsRNA Delivery
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