Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung

Mini Thomas, James J. Lu, Qing Ge, Chengcheng Zhang, Jianzhu Chen, Alexander M. Klibanov

Research output: Contribution to journalArticle

305 Scopus citations

Abstract

High-molecular-mass polyethylenimines (PEIs) are widely used vectors for nucleic acid delivery. We found that removal of the residual N-acyl moieties from commercial linear 25-kDa PEI enhanced its plasmid DNA delivery efficiency 21 times in vitro, as well as 10,000 times in mice with a concomitant 1,500-fold enhancement in lung specificity. Several additional linear PEIs were synthesized by acid-catalyzed hydrolysis of poly(2-ethyl-2-oxazoline), yielding the pure polycations. PEI87 and PEI217 exhibited the highest efficiency in vitro: 115-fold and 6-fold above those of the commercial and deacylated PEI25s, respectively; moreover, PEI87 delivered DNA to mouse lung as efficiently as the pure PEI25 but at a lower concentration and with a 200-fold lung specificity. These improvements stem from an increase in the number of protonatable nitrogens, which presumably results in a tighter condensation of plasmid DNA and a better endosomal escape of the PEI/DNA complexes. As a validation of the potential of such linear, fully deacylated PEIs in gene therapy for lung diseases, systemic delivery in mice of the complexes of a short interfering RNA (siRNA) against a model gene, firefly luciferase, and PEI25 or PEI87 afforded a 77% and 93% suppression of the gene expression in the lungs, respectively. Furthermore, a polyplex of a siRNA against the influenza viral nucleocapsid protein gene and PEI87 resulted in a 94% drop of virus titers in the lungs of influenza-infected animals.

Original languageEnglish (US)
Pages (from-to)5679-5684
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number16
DOIs
StatePublished - Apr 19 2005

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Keywords

  • Flu therapy
  • Influenza
  • Linear polyethylenimine
  • Short interfering RNA
  • Transfection

ASJC Scopus subject areas

  • General

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