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Journal of Virology, June 2000, p. 5320-5328, Vol. 74, No. 11
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Incorporation of Tumor Vasculature Targeting Motifs into Moloney Murine Leukemia Virus Env Escort Proteins Enhances Retrovirus Binding and Transduction of Human Endothelial Cells

Liqiong Liu,1 Ling Liu,1 W. French Anderson,1,2 Robert W. Beart,3 Erlinda M. Gordon,1,2 and Frederick L. Hall1,3,4,*

Gene Therapy Laboratories1 and Departments of Pediatrics2 and Surgery,3 University of Southern California School of Medicine, and the Department of Molecular Pharmacology and Toxicology, University of Southern California School of Pharmacy,4 Los Angeles, California 90033

Received 9 December 1999/Accepted 1 March 2000

Adhesion receptors expressed on the surfaces of tumor-activated endothelial cells provide an advantageous locus for targeting gene therapy vectors to angiogenic tissues and/or tumor vasculature. In this study, we engineered a series of Asn-Gly-Arg (NGR)-containing congeners of the presumptive cell binding motif contained within the ninth type III repeat of fibronectin and displayed these tumor vasculature targeting motifs (TVTMs) within the context of Moloney murine leukemia envelope "escort" proteins. Comparative studies of envelope incorporation into viral particles and evaluation of the cell binding properties of the targeted vectors revealed critical structural features, thus identifying a subset of optimal TVTMs. Utilizing a modified ELISA to evaluate viral binding to target cells, we observed a significant down-regulation of TVTM-virion binding to human endothelial cells following sustained (48-h) exposure to VEGF. Normalized for equivalent titers (106 CFU/ml), as assayed on NIH 3T3 cells, vectors displaying TVTM escort proteins significantly enhanced the transduction efficiency from 12.2 to 37.4% in human KSY-1 endothelial cell cultures (P < 0.001) and from 0.4 to 4.1% in human umbilical vein endothelial cell (HUVEC) cultures (P < 0.001). In summary, these studies utilized an engineering approach to identify a subset of TVTMs that are stably incorporated as envelope "escort" proteins into retroviral vectors and that, by functioning to improve the binding efficiency and transduction of both HUVEC and KSY1 endothelial cells, may have therapeutic potential for targeting gene delivery to the tumor-associated vasculature.

* Corresponding author. Mailing address: Department of Surgery and Gene Therapy Laboratories, University of Southern California School of Medicine, 1975 Zonal Ave. KAM 300, Los Angeles, CA 90089. Phone: (323) 442-1548. Fax: (323) 442-3618. E-mail: fhall{at}genome2.hsc.usc.edu.

Journal of Virology, June 2000, p. 5320-5328, Vol. 74, No. 11
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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