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J Control Release. 2014 May 28;182:1-12. doi: 10.1016/j.jconrel.2014.03.001. Epub 2014 Mar 11.

Quantitative measurement of delivery and gene silencing activities of siRNA polyplexes containing pyridylthiourea-grafted polyethylenimines.

Author information

  • 1Université de Lorraine, CNRS, CRAN, UMR 7039, Campus Sciences, 54500 Vandoeuvre les Nancy, France.
  • 2Laboratoire de Conception et Application de Molécules Bioactives, CNRS - Université de Strasbourg UMR 7199, Faculté de Pharmacie, 74, Route du Rhin, F-67400 Illkirch, France.
  • 3Ecole Supérieure de Biotechnologie de Strasbourg, CNRS - Université de Strasbourg UMR, Bld Sébastien Brant, F-67412 Illkirch, France.
  • 4Laboratoire de Biophotonique et Pharmacologie, CNRS - Université de Strasbourg UMR 7213, Faculté de Pharmacie, 74, Route du Rhin, F-67400 Illkirch, France.
  • 5Laboratoire de Conception et Application de Molécules Bioactives, CNRS - Université de Strasbourg UMR 7199, Faculté de Pharmacie, 74, Route du Rhin, F-67400 Illkirch, France.. Electronic address: zuber@unistra.fr.

Abstract

The activity of synthetic interfering nucleic acids (siRNAs) relies on the capacity of delivery systems to efficiently transport nucleic acids into the cytosol of target cells. The pyridylthiourea-grafted 25KDa polyethylenimine (πPEI) is an excellent carrier for siRNA delivery into cells and it was extensively investigated in this report. Quantification of the siRNA-mediated gene silencing efficiency indicated that the πPEI specific delivery activity at the cell level may be measured and appears relatively constant in various cell lines. Delivery experiments assaying inhibitors of various entry pathways or concanamycin A, an inhibitor of the H(+)/ATPase vacuolar pump showed that the πPEI/siRNA polyplexes did not require any specific entry mode but strongly relied on vacuolar acidification for functional siRNA delivery. Next, πPEI polyplexes containing a siRNA targeting the transcription factor HIF-1α, known to be involved in tumor progression, were locally injected into mice xenografted with a human glioblastoma. A 55% reduction of the level of the target mRNA was observed at doses comparable to those used in vitro when the πPEI delivery activity was calculated per cell. Altogether, our study underscores the usefulness of "simple"/rough cationic polymers for siRNA delivery despite their intrinsic limitations. The study underscores as well as that bottom-up strategies make sense. The in vitro experiments can precede in vivo administration and be of high value for selection of the carrier with enhanced specific delivery activity and parallel other research aiming at improving synthetic delivery systems for resilience in the blood and for enhanced tissue-targeting capacity.

KEYWORDS:

Glioblastoma; In vivo; Polyethylenimine; Polyplexes; siRNA delivery

PMID:
24631860
DOI:
10.1016/j.jconrel.2014.03.001
[PubMed - indexed for MEDLINE]
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