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Departments of ¹ Biomedical Engineering and ² Radiation Oncology, Duke University, Durham, NC

Requests for Reprints: Fan Yuan, Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Duke University, Durham, NC 27708. Phone: (919) 660-5411; Fax: (919) 684-4488. E-mail: fyuan{at}acpub.duke.edu

Intratumoral injection is a routine method for local viral gene delivery that may improve interstitial transport of viral vectors in tumor tissues and reduce systemic toxicity. However, the concentration of transgene products in normal organs, such as in the liver, may still exceed normal tissue tolerance if the products are highly toxic. The elevated concentration in normal tissues is likely to be caused by the dissemination of viral vectors from the tumor. Therefore, we investigated transgene expression in the liver, the serum, and a mouse mammary carcinoma (4T1) in mice after intratumoral injection of adenoviral vectors for mouse interleukin-12, luciferase, enhanced green fluorescence protein, or ß-galactosidase. We also performed numerical simulations of virus transport in tumors after intratumoral injection, based on the Krogh cylinder model. Our experimental data and numerical simulations demonstrated that virus dissemination was significant in mice and it occurred mainly during the intratumoral injection. To reduce virus dissemination, we mixed these vectors with a viscous alginate solution and injected the mixture into the tumors. Our data showed that the alginate solution could significantly reduce virus dissemination while having minimal effects on transgene expression in tumors and on interleukin-12-induced tumor growth delay. These data suggest that virus dissemination is a potential problem in local viral gene therapy of cancer and that the dissemination could be significantly reduced by the alginate solution without compromising the efficacy of gene therapy.

Grant support: National Science Foundation (BES-9984062) and the NIH (CA81512).

Received 3/27/03; revised 7/20/03; accepted 8/ 7/03.

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