Gene therapy has shown promise in a number of cancer treatment studies. However, certain drawbacks such as uncontrolled gene delivery and random gene integration have limited its potential use in the clinical setting. By utilizing magnetic nanoparticles as vehicles for genetic delivery, researchers in China have succeeded in overcoming several obstacles associated with gene therapy and increased the efficacy of treatment for hepatic cellular carcinoma (HCC).
The study, carried out by investigators at Southeast University in China, involves the delivery of suicide genes directly into HCC cells. Transcription of the genes is enhanced by several factors, including tissue-specific promoter elements. The treatment proved effective in significantly reducing the size of hepatic tumors in vitro and in vivo, resulting in a promising alternative to current treatment methods.
Magnetic nanoparticles deliver tissue-specific suicide genes
The delivery system is based on iron oxide nanoparticles measuring 20-30 nm, whose surface is decorated with polyethylenimine (PEI). The PEI renders the surface charge positive, allowing the particles to strongly bind a large amount of DNA. For their purposes, researchers relied on passive delivery of the nanoparticles, utilizing their tendency to collect in the liver after injection and pass through tumor blood vessels to accumulate within the tumor.
The nanoparticles delivered a plasmid encoding a suicide gene, specifically, herpes simplex virus thymidine kinase (HSV-tk). Tumor-specific expression of HSV-tk was induced by an upstream flanking sequence consisting of alpha-fetoprotein (AFP) promoter controlled by a 5’ hypoxia response element (HRE). The AFP promoter is reactivated in HCC cells, but not in healthy cells. HRE is bound by hypoxia-inducible factor-1 (HIF-1) in the hypoxic tumor environment, boosting transcription from the downstream AFP promoter. As a result, HSV-tk is expressed – and its expression is significantly enhanced – specifically in HCC cells.
Synergistic effects seen with multimodal therapy
In addition to the suicide gene, researchers treated cells with ganciclovir (GCV). GCV is an anti-viral drug that is non-toxic to mammalian cells. When phosphorylated by HSV-tk, however, it is capable of disrupting DNA synthesis. Because HSV-tk was only expressed in tumor cells, the observed cytotoxic effects of GCV were limited to HCC cells.
By exposing tumor cells to hyperthermia induced by the effect of alternating magnetic frequency on the nanoparticles, researchers introduced yet another level of toxicity. Hyperthermia treatment was localized to the tumor by magnetic targeting, thus avoiding heat-induced damage to surrounding tissue.
In many cases, HCC cells are resistant to standard radiation and chemotherapy protocols. The current study introduces a viable course of treatment that involves neither of these, yet provides significant tumor-specific toxicity. By combining gene therapy with biocompatible magnetic nanoparticles, investigators devised a novel approach with important implications. In addition to offering an alternative that is far less damaging to healthy tissue, they have provided a way to target treatment and delivery, making this a viable alternative therapy against several different types of cancer.
A full report of the data and results can be found in “Nanotechnology”.
