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Conjugating Phosphospermines to siRNAs for Improved Stability in Serum, Intracellular Delivery and RNAi-Mediated Gene Silencing.
MedLine Citation:
PMID:  23148419     Owner:  NLM     Status:  Publisher    
siRNAs are usually formulated with cationic polymers or lipids to form supramolecular particles capable of binding and crossing the negatively charged cell membrane. However, particles hardly diffuse through tissues when administered in vivo. We therefore are developing cationic siRNAs, composed of an antisense sequence annealed to an oligophosphospermine-conjugated sense strand. Cationic siRNAs have been previously shown to display gene silencing activity in human cell line (Nothisen et al. J. Am. Chem. Soc.2009). We have improved the synthesis, purification and characterization of oligospermine-oligoribonucleotide conjugates which provide cationic siRNAs with enhanced biological activity. We show data supporting their carrier-free intracellular delivery in a molecular, soluble state. Additional results on the relationship between global charge, uptake and silencing activity confirm the requirement for an overall positive charge of the conjugated siRNA in order to enter cells. Importantly, conjugated siRNAs made of natural phosphodiester nucleotides are protected from nuclease degradation by the oligophosphospermine moiety, operate through the RNAi mechanism and mediate specific gene silencing at submicromolar concentration in the presence of serum.
Clément Paris; Valérie Moreau; Gaëlle Deglane; Loukmane Karim; Bernard Couturier; Marie-Elise Bonnet; Valérie Kedinger; Mélanie Messmer; Anne-Laure Bolcato-Bellemin; Jean-Paul Behr; Patrick Erbacher; Nathalie Lenne-Samuel
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-14
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Polyplus-tranfection SA, Bioparc, Boulevard S. Brant, Illkirch, 67401, France.
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