Brief Articles
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World J Gastroenterol. Jun 14, 2009; 15(22): 2754-2762
Published online Jun 14, 2009. doi: 10.3748/wjg.15.2754
Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo
Michael A van Geer, Conny T Bakker, Naoya Koizumi, Hiroyuki Mizuguchi, John G Wesseling, Ronald PJ Oude Elferink, Piter J Bosma
Michael A van Geer, Conny T Bakker, John G Wesseling, Piter J Bosma, Ronald PJ Oude Elferink, Liver Center of the Academic Medical Center of the University of Amsterdam, Meibergdreef 69/71, 1105BK Amsterdam, The Netherlands
Naoya Koizumi, Hiroyuki Mizuguchi, Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, 7-6-8 Saito, Asagi, Ibaraki, Osaka 567-0085, Japan
Author contributions: van Geer MA and Bakker CT performed the majority of the experiments; Koizumi N and Mizuguchi H provided vital reagents and analytical tools; Wesseling JG provided financial support for this work; Oude Elferink RPJ and Bosma PJ designed the study and wrote the manuscript.
Correspondence to: Dr. Piter J Bosma, Liver Center AMC, University of Amsterdam, Meibergdreeg 69/71, 1105BK Amsterdam, The Netherlands.
Telephone: +31-20-5668850
Fax: +31-20-5669190
Received: February 6, 2009
Revised: April 29, 2009
Accepted: May 6, 2009
Published online: June 14, 2009

AIM: To generate an adenoviral vector specifically targeting the EphA2 receptor (EphA2R) highly expressed on pancreatic cancer cells in vivo.

METHODS: YSA, a small peptide ligand that binds the EphA2R with high affinity, was inserted into the HI loop of the adenovirus serotype 5 fiber knob. To further increase the specificity of this vector, binding sites for native adenoviral receptors, the coxsackie and adenovirus receptor (CAR) and integrin, were ablated from the viral capsid. The ablated retargeted adenoviral vector was produced on 293T cells. Specific targeting of this novel adenoviral vector to pancreatic cancer was investigated on established human pancreatic cancer cell lines. Upon demonstrating specific in vitro targeting, in vivo targeting to subcutaneous growing human pancreatic cancer was tested by intravenous and intraperitoneal administration of the ablated adenoviral vector.

RESULTS: Ablation of native cellular binding sites reduced adenoviral transduction at least 100-fold. Insertion of the YSA peptide in the HI loop restored adenoviral transduction of EphA2R-expressing cells but not of cells lacking this receptor. YSA-mediated transduction was inhibited by addition of synthetic YSA peptide. The transduction specificity of the ablated retargeted vector towards human pancreatic cancer cells was enhanced almost 10-fold in vitro. In a subsequent in vivo study in a nude (nu/nu) mouse model however, no increased adenoviral targeting to subcutaneously growing human pancreas cancer nodules was seen upon injection into the tail vein, nor upon injection into the peritoneum.

CONCLUSION: Targeting the EphA2 receptor increases specificity of adenoviral transduction of human pancreatic cancer cells in vitro but fails to enhance pancreatic cancer transduction in vivo.

Keywords: Pancreatic cancer, Adenoviruses, Ephrin A receptor, Targeting, Genetic transduction