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Imaging of Adenoviral-Directed Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Expression in Mice with Radiolabeled Ganciclovir

Crump Institute for Biological Imaging; UCLA/DOE Laboratory of Structural Biology and Molecular Medicine; Department of Molecular and Medical Pharmacology, Division of Nuclear Medicine; Molecular Biology Institute; Department of Biomathematics; UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California

Correspondence: For correspondence or reprints contact: Sanjiv S. Gambhir, UCLA School of Medicine, 700 Westwood Plaza, A-222B CIBI, Los Angeles, CA 90095-1770.

ABSTRACT

We are developing procedures to repeatedly and noninvasively image the expression of transplanted reporter genes in living animals and in patients, using PET. We have investigated the use of the Herpes Simplex Virus type 1 thymidine kinase gene (HSV1-tk)as a reporter gene and [8-¹⁴C]-ganciclovir as a reporter probe. HSV1-tk, when expressed, leads to phosphorylation of [8-¹⁴C]-ganciclovir. As a result, specific accumulation of phosphorylated [8-¹⁴C]-ganciclovir should occur almost exclusively in tissues expressing the HSV1-tk gene. Methods: An adenoviral vector was constructed carrying the HSV1-tk gene along with a control vector. C6 rat glioma cells were infected with either viral vector and uptake of [8-³H]-ganciclovir was determined. In addition, 12 mice were injected with varying levels of either viral vector. Adenovirus administration in mice leads primarily to liver infection. Forty-eight hours later the mice were injected with [8-¹⁴C]-ganciclovir, and 1 hr later the mice were sacrificed and biodistribution studies performed. Digital whole-body autoradiography also was performed on separate animals. HSV1-tk expression was assayed, using both normalized HSV1-tk mRNA levels and relative HSV1-TK enzyme levels, in both the cell culture and murine studies. Results: Cell culture, murine tissue biodistribution and murine in vivo digital whole-body autoradiography all demonstrate the feasibility of HSV1-tk as a reporter gene and [8-¹⁴C]-ganciclovir as an imaging reporter probe. A good correlation (r2 = 0.86) between the [8-¹⁴C]-ganciclovir percent injected dose per gram tissue from HSV1-tk positive tissues and HSV1-TK enzyme levels in vivo was found. An initial study in mice with [8-¹⁸F]-fluoroganciclovir and micro PET imaging supports further investigation of [8-¹⁸F]-fluoroganciclovir as a PET reporter probe for imaging HSV1-tk gene expression. Conclusion:These results demonstrate the feasibility of using [8-¹⁴C]-ganciclovir as a reporter probe for the HSV1-tk reporter gene, using an in vivo adenoviral mediated gene delivery system in a murine model. The results form the foundation for further investigation of [8-¹⁸F]-fluoroganciclovirfor noninvasive and repeated imaging of gene expression with PET.

Key Words: reporter gene • imaging • PET • thymidine kinase • gene expression

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