Multifunctional peptide-PEG intercalating conjugates: Programmatic of gene delivery to the blood-brain barrier

Hongwei Zhang, Trevor Gerson, Michelle L. Varney, Rakesh K. Singh, Serguei V. Vinogradov

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Purpose To enhance transfection efficacy of pDNA through the application ofmultifunctional peptide-PEG-tris-acridine conjugates ( pPAC) and the formation of biodegradable core-shell polyplexes for gene delivery to the blood-brain barrier (BBB). Methods pPAC-mediated transfection was compositionally optimized in mouse BBB cells (bEnd.3). Cellular uptake and trafficking, and brain accumulation of pDNA was evaluated by fluorescent imaging and histochemistry. We constructed anti- MRP4 siRNA-producing vectors and evaluated the efficacy of MRP4 down-regulation of MRP4 by Western blot and qPCR, and its effect on the uptake of 3H-AZT, an MRP4 substrate. Results A core-shell gene delivery system (GDS) was assembled from pDNA and pPAC, carrying multifunctional peptides with NLS, TAT, and brain-specific BH, or ApoE sequences, and biodegradable pLPEI polyamine. This GDS demonstrated better cellular and nuclear accumulation, and a 25-fold higher transfection efficacy in slow-dividing bEnd.3 cells compared to ExGen500. Inclusion of brain-targeting pPAC enhanced in vivo accumulation of functional pDNA in brain capillaries. Treatment by encapsulated anti-MRP4 siRNAproducing pDNA caused transient down-regulation of MRP4, and, after intravenous injection in Balb/c mice, enhanced AZT uptake in the brain by 230-270%. Conclusions The pPAC represent novel efficient components of GDS that could find various gene therapy applications, including genetic modulation of the BBB.

Original languageEnglish (US)
Pages (from-to)2528-2543
Number of pages16
JournalPharmaceutical Research
Issue number12
StatePublished - Dec 2010


  • AZT
  • ApoE peptide
  • Blood-brain barrier
  • Brain capillary endothelial cells
  • Brain-homing peptide
  • Intercalating complex
  • MRP4
  • NLS peptide
  • Peptide-PEG conjugate
  • Plasmid DNA
  • TAT peptide

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


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