Short biodegradable polyamines for gene delivery and transfection of brain capillary endothelial cells

Hongwei Zhang, Serguei V Vinogradov

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

With the goal of rational design of systemic gene delivery system and efficient transfection of capillary endothelial cells forming the blood-brain barrier (BBB), we synthesized several short polyamines with reducible disulfide backbones for pDNA packaging, internalization and consequent release from endosomal compartments. The synthetic cationic polymers prepared from short linear PEI (pLPEI), triethylenetetramine (pTETA), and spermine (pSPE), demonstrated very low toxicity, good condensation capacity, and high levels of pDNA protection, producing small particulate nanoformulations. Mild reduction of the disulfide backbone allowed complete release of pDNA from these polyplexes. In vitro transfection of murine brain capillary endothelial bEnd.3 cells with pSPE, pTETA, and pLPEI polyplexes was 2.3-4.9 times more effective compared with the non-degradable LPEI 22. kDa reagent (ExGen500) in the presence of serum. Their transfection ability was noticeably decreased following inhibition of the cellular reduced glutathione (GSH). After cellular uptake of biodegradable polyplexes, a disperse distribution of labeled pDNA in the cytoplasm of transfected cells was observed in contrast to ExGen500. Based on these polyamines, novel multifunctional polyplexes have been developed for efficient nuclear delivery of pDNA by co-application of NLS peptide and PEG-modified intercalating conjugates. Significant increase of nuclear accumulation was observed, and the transfection of bEnd.3 cells was additionally enhanced nearly 2-fold, demonstrating 8.5-, 6.3- and 3.7-fold better levels for pLPEI, pTETA, and pSPE, respectively, compared to ExGen500. Following brain-specific targeting, these safe and effective polyplexes may be converted into systemic nanocarriers for gene delivery and transfection of the BBB.

Original languageEnglish (US)
Pages (from-to)359-366
Number of pages8
JournalJournal of Controlled Release
Volume143
Issue number3
DOIs
StatePublished - May 1 2010

Fingerprint

Polyamines
Transfection
Trientine
Endothelial Cells
Spermine
Brain
Genes
Blood-Brain Barrier
Disulfides
Nuclear Localization Signals
Gene Transfer Techniques
Product Packaging
Glutathione
Polymers
Cytoplasm
Serum

Keywords

  • Biodegradable polyamines
  • Blood-brain barrier
  • Gene delivery
  • NLS peptide
  • Non-viral transfection
  • Nuclear targeting

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Short biodegradable polyamines for gene delivery and transfection of brain capillary endothelial cells. / Zhang, Hongwei; Vinogradov, Serguei V.

In: Journal of Controlled Release, Vol. 143, No. 3, 01.05.2010, p. 359-366.

Research output: Contribution to journalArticle

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