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Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma

Cancer Gene Therapy volume 20, pages 290–297 (2013)Cite this article

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Abstract

Cancer gene therapy has great potential for decreasing tumor-induced mortality but has been clinically limited by non-targeted and insufficient gene transfer. We evaluated gene therapy targeting hepatocellular carcinoma (HCC) using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene system and the tissue inhibitor of metalloproteinase 3 (Timp3) gene. Ultrasound-targeted microbubble destruction (UTMD) targeted gene delivery to the tumor tissue, and the α-fetoprotein promoter targeted HSVtk expression to the HCC cells. Human HepG2 cells transfected with the HSVtk or Timp3 gene demonstrated a reduction in cell viability by >40% compared with the vector control. Cell viability was further inhibited by over 50% with co-transfection of the genes. HepG2 cells were inoculated subcutaneously into athymic mice to induce tumors. UTMD-mediated delivery of HSVtk or Timp3 suppressed tumor growth by >45% and increased survival of tumor-bearing animals (P<0.01 vs vector control). Co-delivery of the genes resulted in a further 30% improvement in tumor suppression and significant extension of animal survival (P<0.01 vs vector control). Targeted gene delivery increased the number of apoptotic cells and decreased the vascular density of the tumors. Targeted co-delivery of the genes synergistically improved the antitumor effects and may provide an effective therapy for HCC.

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Acknowledgements

This work was funded by grants from the Canadian Institutes of Health Research (MOP119507 to RKL) and the National Natural Science Foundation of China (No. 30901821 and 81172136 to JX).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China

    B-F Yu & J Xie

  2. Toronto General Research Institute, University Health Network, Toronto, ON, Canada

    J Wu, Y Zhang & R-K Li

  3. Department of Surgery, University of Toronto, Toronto, ON, Canada

    J Wu, Y Zhang & R-K Li

  4. Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan

    H-W Sung

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  1. B-F Yu
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Correspondence to J Xie or R-K Li.

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Yu, BF., Wu, J., Zhang, Y. et al. Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma. Cancer Gene Ther 20, 290–297 (2013). https://doi.org/10.1038/cgt.2013.19

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