Selective targeting of adenovirus to alphavbeta3 integrins, VEGFR2 and Tie2 endothelial receptors by angio-adenobodies.

Abstract

Tumor angiogenesis is a prominent mechanism, driving the development and progression of solid tumors and the formation of cancer cell metastasis. Newly formed tumor vessels represent an elective target for the activity and the delivery of cancer therapeutics. We targeted adenovirus (Ad5) to endothelial receptors which are up-regulated during the formation of new blood vessels, to enhance the efficiency of anticancer gene therapy applications. Bifunctional angio-adenobodies were constructed by the fusion of a single chain antibody directed against the adenoviral fiber knob, to different peptides recognizing the alpha(v)beta(3) integrins, VEGFR2 and Tie2 receptors on endothelial cells. The angio-adenobodies were coupled to the adenoviral vector, containing luciferase and GFP as reporter genes. In vitro data showed selective targeting of the Ad5 to the endothelial receptors both in mouse (H5V) and human cell lines (HUVEC). H5V cells, refractory to Ad5 infection, showed high level of luciferase expression when cells were infected with targeted virus. Viral transgene expression increased in HUVEC cells when cells were infected with Ad5 conjugated with angio-adenobody thereby demonstrating the affinity of the peptides for human endothelial cells also. In vivo data obtained from mice bearing a C26 colon carcinoma subcutaneously show viral transgene expression only in tumors infected with angio-adenobodies retargeted adenovirus. The results of the present study demonstrate that endothelial targeted angio-adenobodies represent a versatile tool to direct adenovirus from its native receptors to the integrins alpha(v)beta(3), VEGFR2 and Tie2 receptors that are fundamental in many angiogenesis related diseases such as cancer.

• Authors: Hidde J Haisma, Gera K Kamps, Arend Bouma, Tessa M Geel, Marianne G Rots, Anu Kariath, Anna Rita Bellu
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 391 Issue 1-2 Pg. 155-61 (May 31 2010) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 20211716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Integrin alphaVbeta3
• Peptides
• Single-Chain Antibodies
• Receptor, TIE-2
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adenoviridae (immunology, pathogenicity)
• Amino Acid Sequence
• Animals
• Antineoplastic Agents (administration & dosage, immunology)
• Cell Line
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• Endothelial Cells (immunology, metabolism)
• Humans
• Integrin alphaVbeta3 (metabolism)
• Mice
• Mice, Inbred BALB C
• Peptides (administration & dosage, immunology)
• Receptor, TIE-2 (metabolism)
• Single-Chain Antibodies (administration & dosage)
• Up-Regulation (immunology)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)