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Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector

Cancer Gene Therapy volume 9, pages 260–266 (2002)Cite this article

Abstract

The use of adenoviral vectors for therapeutic delivery of genes via pulmonary application poses several problems in terms of immune responses. The purpose of this study was to determine whether polyethylenimine (PEI), a polycationic DNA carrier, can be used to deliver the IL-12 gene into the lungs of mice having microscopic osteosarcoma (OS) lung metastases. Incubation of SAOS-LM6 cells in vitro with PEI containing the murine IL-12 (mIL-12) gene (PEI:IL-12) resulted in expression of both the p35 and p40 subunits of IL-12 mRNA and production of mIL-12 protein. Using our newly developed OS nude mouse model, we demonstrated that treatment of mice using intranasal PEI:IL-12 resulted in significant IL-12 mRNA expression in the lung but not the liver. Furthermore, plasma IL-12 was undetectable after up to 4 weeks of intranasal PEI:IL-12 therapy given twice weekly. No IL-12 expression was seen following intranasal PEI therapy alone. The number of lung metastases in animals that received intranasal PEI:IL-12 twice weekly for 4 weeks starting 6 weeks after tumor inoculation was significantly decreased (median, 11; range, 0–47) compared with those that received PEI alone (median, 89; range, 2 to >200; P=.012). Also, the size of the nodules was significantly smaller in the PEI:IL-12–treated animals, with 90% measuring ≤0.5 mm in diameter compared with 56% in the PEI-alone group. Animals that received PEI alone also had numerous large nodules (3–6 mm) throughout the lungs. Intranasal therapy is a noninvasive way to administer agents and has the advantage of targeting the pulmonary region, resulting in higher concentrations in the tumor area. Additionally, delivery of IL-12 to the lung via the airway using PEI may avoid systemic toxicity. Because OS metastasizes almost exclusively to the lung, this may be a novel approach to the treatment of pulmonary OS metastases.

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Acknowledgements

This study was supported in part by Grant CA42992 [to ESK] a grant from the Texas Higher Education Coordinating Board [to ESK and CLD], National Institutes of Health Core Grant CA-16672, and a grant from the Clayton Foundation (to CLD).

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Eugenie S Kleinerman

  2. Department of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Shu-Fang Jia, Laura L Worth, Zhichao Zhou & Eugenie S Kleinerman

  3. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, 77030, Texas, USA

    Charles L Densmore & Bo Xu

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  1. Shu-Fang Jia
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  2. Laura L Worth
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  5. Zhichao Zhou
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  6. Eugenie S Kleinerman
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Correspondence to Eugenie S Kleinerman.

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Jia, SF., Worth, L., Densmore, C. et al. Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector. Cancer Gene Ther 9, 260–266 (2002). https://doi.org/10.1038/sj.cgt.7700432

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