Abstract
Treatment of cancers in the lung remains a critical challenge in the clinic for which gene therapy could offer valuable options. We describe an effective approach through systemic injection of engineered polymer/DNA nanoparticles that mediate tumor-specific expression of a therapeutic gene, under the control of the cancer-selective progression elevated gene 3 (PEG-3) promoter, to treat tumors in the lungs of diseased mice. A clinically tested, untargeted, polyethylenimine carrier was selected to aid rapid transition to clinical studies, and a CpG-free plasmid backbone and coding sequences were used to reduce inflammation. Intravenous administration of nanoparticles expressing murine single-chain interleukin 12, under the control of PEG-3 promoter, significantly improved the survival of mice in both an orthotopic and a metastatic model of lung cancer with no marked symptoms of systemic toxicity. These outcomes achieved using clinically relevant nanoparticle components raises the promise of translation to human therapy.
Highlights
Treatment of cancers in the lung remains a critical challenge in the clinic for which gene therapy could offer valuable options
In order to demonstrate functional expression of IL-2 and IL-12, we performed a CTLL-2 expression assay. Both human and murine IL-2 can act on CTLL-2 cells and mIL-12 has been shown to have a proliferative effect in the presence of IL-2
The results showed that undiluted culture supernatant from LL/2 cells transfected with nanoparticles expressing murine IL-12 and human or mouse IL-2, caused equivalent proliferation of CTLL-2 cells, demonstrated expression of active IL-2 and mIL-12, whereas a negative control had no effect (Fig. S3B)
Summary
Treatment of cancers in the lung remains a critical challenge in the clinic for which gene therapy could offer valuable options. Intravenous administration of nanoparticles expressing murine single-chain interleukin 12, under the control of PEG-3 promoter, significantly improved the survival of mice in both an orthotopic and a metastatic model of lung cancer with no marked symptoms of systemic toxicity These outcomes achieved using clinically relevant nanoparticle components raises the promise of translation to human therapy. In this study we tested the delivery efficiency, treatment efficacy and safety of systemically administered l-PEI/DNA nanoparticles that express IL-12, alone or in combination with other genes, Herpes Simplex Virus 1 thymidine kinase (HSV1-tk) and IL-2, in two mouse models that represent primary lung tumours and metastatic tumours
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