Poster Presentation 11th Australian Peptide Conference 2015

The design and optimization of bombesin-poly-L-lysine dendron fusions for tumour-targeted oligonucleotide delivery  (#107)

Anjuman Ara Begum 1 , Peter M Moyle 1 2 , Istvan Toth 1 2 3
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Saint Lucia, QLD, Australia
  2. School of Pharmacy, The University of Queensland, Woolloongabba, , QLD, Australia
  3. Institute of Molecular Bioscience, The University of Queensland, Saint Lucia, QLD, Australia

Oligonucleotide therapy is an emerging technique for treating hereditary and acquired genetic diseases.1 The main challenge for oligonucleotide therapy is the lack of safe and efficient delivery systems capable of delivering therapeutic genes to their site of action.2 Receptor targeted non-viral gene delivery system is a promising strategy for the targeted delivery of therapeutic oligonucleotides. These systems afford improved efficacy compared to non-targeted delivery systems, which affords advantages including improved efficacy, and reduced off-target effects, while allowing lower, and more cost effective oligonucleotide doses to be administered.3

In this present work, bombesin peptide has been used to selectively target the gastrin releasing peptide (GRP) receptor which is overexpressed by several common cancers (e.g. breast, lung, pancreatic, prostate and colon).3 The peptide based multicomponent oligonucleotide delivery systems targeting GRP receptors consist of a short length bombesin peptide (BBN (6-14)) and a full length bombesin peptide with a cationic poly-L-lysine dendron attached (8+ charge). Full length and truncated bombesin peptide N-terminal fusions with a poly-L-lysine dendron were successfully synthesized and characterized for plasmid DNA (pDNA) delivery. Both of these systems efficiently condensed pDNA. According to flow cytometry and confocal microscopy analysis, both delivery systems demonstrated significant uptake into PC-3 cells, which express GRP receptors. Competition with an excess of wild-type bombesin peptide inhibited the uptake of the delivery systems, suggesting that their internalization was due to GRP receptor uptake. No difference in cell uptake and pDNA delivery was observed between the full-length and truncated bombesin containing delivery systems. This suggested that the truncated bombesin peptide could be used for the efficient targeted delivery of oligonucleotides into tumour cells.

  1. Guo X, Huang L. Recent Advances in Non-viral Vectors for Gene Delivery. Acc Chem Res.2012; 45(7): 971-979
  2. Zhao L, Wu J, Zhou H, et al. Local gene delivery for cancer therapy. Curr Gene Ther. 2011;11:423–432
  3. Hao Yang H, Cai H, Wan L, et al. Bombesin Analogue-Mediated Delivery Preferentially Enhances the Cytotoxicity of a Mitochondria-Disrupting Peptide in Tumor Cells. PLoS One. 2013; 8(2): e57358.