Duramycin-porphyrin conjugates for targeting of tumour cells using photodynamic therapy.
Duramycin, through binding with phosphatidylethanolamine (PE), has been shown to be a selective molecular probe for the targeting and imaging of cancer cells. Photodynamic therapy aims to bring about specific cytotoxic damage to tumours through delivery of a photosensitising agent and light irradiation. Conjugation to biological molecules that specifically target cancer has been shown to increase photosensitiser (PS) selectivity and decrease damage to surrounding normal tissue. The aim of this study was to target tumour cells with a PE-specific PS therefore duramycin was conjugated to a porphyrin based PS which was achieved via direct reaction with the ε-amino group on the lysine residue near duramycin's N-terminal. The compound was subsequently purified using RP-HPLC and confirmed using mass spectrometry. Binding of the conjugate to ovarian and pancreatic cancer cell lines was assessed by flow cytometry. Light irradiation with a light fluence of 7.5J/cm(2) was delivered to conjugate treated cancer cells and cell proliferation analysed by MTT assay. The conjugate detected PE on all 4 cancer cell lines in a concentration dependent manner and conjugate plus irradiation effectively reduced cell proliferation at concentrations ≥0.5μM, dependent on cancer cell line. Reduction in cell proliferation by the irradiated conjugate was enhanced over unconjugated duramycin in A2780, AsPC-1 and SK-OV-3 (p<0.05). In this study we have shown that a duramycin-porphyrin conjugate retained good binding affinity for its target and, following irradiation, reduced cell proliferation of pancreatic and ovarian cancer cell lines.
Hull York Medical School, University of Hull, Hull HU6 7RX, UK.
Laura J
LJ
Broughton
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 2AJ, UK.
Francesca
F
Giuntini
Department of Chemistry, University of Hull, Hull, HU6 7RX, UK.
Huguette
H
Savoie
Department of Chemistry, University of Hull, Hull, HU6 7RX, UK.
Francesca
F
Bryden
Department of Chemistry, University of Hull, Hull, HU6 7RX, UK.
Ross W
RW
Boyle
Hull York Medical School, University of Hull, Hull HU6 7RX, UK.
Anthony
A
Maraveyas
School of Life Sciences, University of Hull, Hull, HU6 7RX, UK. Electronic address: L.A.Madden@hull.ac.uk.
Leigh A
LA
Madden
D001430:Bacteriocins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011166:Porphyrins / Q000737:chemistry*
D001430:Bacteriocins; D010455:Peptides; D010714:Phosphatidylethanolamines; D017319:Photosensitizing Agents; D011166:Porphyrins; C040522:duramycin; C483858:phosphatidylethanolamine
Cancer; Duramycin; Phosphatidylethanolamine; Photodynamic therapy; Porphyrin