Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer

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In this work, a stimuli-responsive stem cell-based gene therapy was developed to enhance the treatment of ovarian cancer. In particular, MCNPs were used for the dual purpose of delivering a heat-inducible plasmid encoding TRAIL and remotely activating TRAIL secretion in the engineered AD-MSCs via mild magnetic hyperthermia. As such, by combining the tumor tropism of the AD-MSCs with the spatiotemporal MCNP-based delivery and activation of TRAIL expression, this platform provides an attractive means with which to enhance our control over the activation of stem cell-based gene therapies. Importantly, we demonstrated that the process of engineering the AD-MSCs did not significantly affect their innate proliferation, differentiation, and tumor homing capabilities. Moreover, mild magnetic hyperthermia resulted in the selective expression of TRAIL in the engineered MSCs, thereby inducing significant ovarian cancer cell apoptosis and death in vitro and in vivo.

Previous studies have demonstrated that mild hyperthermia can be used to activate genes [50-53]. However, these reports have primarily focused on simple proof-of-concept studies wherein reporter genes were activated in cancer cells. For instance, Ortner et al. used iron oxide nanoparticles to deliver a heat-inducible luciferase or GFP plasmid to Human embryonic kidney 293 (HEK293) cells [51]. In particular, they demonstrated that they could regulate reporter gene expression in vitro using magnetic hyperthermia. On the other hand, Yamaguchi et al. demonstrated a heat-inducible system for cancer treatment, wherein magnetic nanoparticles were used to deliver a heat-inducible plasmid encoding tumor necrosis factor alpha (TNF-α) [50]. In this case, these magnetic nanoparticle-plasmid complexes were delivered directly to the human lung adenocarcinoma cells (A549) in order to induce apoptosis of the lung adenocarcinoma cells. Using this system, the authors were able to control the expression of TNF-α in the transfected cancer cells both in vitro and in vivo using magnetic hyperthermia, thereby demonstrating a local and effective cancer therapy.

While promising, these previous demonstrations are still plagued by the difficulty of actually delivering the magnetic nanoparticles and plasmids to the tumor in vivo. As such, they would be unable to target cancers in distinct parts of the body where the cancer has metastasized and, as a result, would be extremely difficult to translate to the clinic. Moreover, the cell lines used in these previous studies are relatively easy to transfect. Addressing these challenges, we have demonstrated an advanced heat-activated gene therapies in this report, wherein we engineered stem cells in order to take advantage of their innate tumor targeting ability. In particular, we are the first to report the use of mild magnetic hyperthermia to remotely activate a heat-inducible gene in stem cells. In the future, we envision that the biocompatible mSi shell of the MCNP can be filled with chemotherapy in order to enhance the effect of TRAIL. For instance, while the delivery of TRAIL has already been shown to be effective against cancer cells that have acquired resistance to conventional chemotherapy via p53 inactivation, tumor cells have also developed various mechanisms to escape TRAIL-induced apoptosis [1]. To this end, a number of studies have identified novel combinations that could be used with TRAIL to potentiate its therapeutic efficacy. For instance, Kelly et al. has demonstrated that the pretreatment of prostate cancer cells with doxorubicin can increase their sensitivity to TRAIL [54]. 

In conclusion, we have successfully combined synthetic biology with nanotechnology, wherein mild magnetic hyperthermia was used to specifically activate genes in stem cells. Owing to the great potential of stem cells, the implications of this study go well beyond cancer applications, and can potentially be used for a host of applications that range from the stimuli-guided differentiation of stem cells for the treatment of injuries such as spinal cord or traumatic brain injury to other diseases such as those involving inflammation, wherein stem cells can be engineered to conditionally secrete anti-inflammatory molecules. As such, we have demonstrated a stimuli-responsive stem cell-based gene therapy using multifunctional MCNPs, which could have great potential for both cancer and other regenerative applications.