Brain tumors are one of the most challenging forms of cancer to treat. Glioblastoma is the most aggressive type of brain tumor and despite medical intervention the median survival is only 12-15 months. Surgery is an acceptable treatment option if the tumor location is amenable to removal, but often the infiltrative nature of glioblastoma prevents complete resection. Radiation therapy and chemotherapy are also viable treatment options, but they are plagued by side effects ranging from minor reactions like nausea and hair loss to extreme complications such as personality changes, loss of physical ability, or cognitive dysfunction. Therefore, there is a significant need for advances in care not only to improve survival but also to improve quality of life post treatment. RNA interference (RNAi) has emerged as a promising alternative to conventional therapy. In RNAi, short double-stranded ribonucleic acid (RNA) sequences delivered to a cell induce the encoded messenger RNA to be degraded, thereby silencing gene expression. Targeting genes specific to cancer offers an intriguing method for either inducing cancerous cell death or sensitizing tumors to other forms of therapy. Unfortunately, it is difficult to deliver siRNA to glioblastoma and other brain tumors because it must first cross the blood-brain barrier, enter the cancerous cells, and then escape the endosome to render its effect. In addition, siRNA has a short half-life in blood because it is rapidly degraded by RNases. The proposed work seeks to overcome these limitations by densely loading siRNA onto gold nanoparticles, thereby protecting it from RNase degradation and enabling it to cross the blood-brain barrier and enter brain tumors. The efficacy of RNAi mediated by these siRNA-gold nanoparticle conjugates (siRNA-AuNPs) will be evaluated using in vivo models of glioblastoma. First, optical imaging methods will be incorporated to track siRNA-AuNP delivery to tumors in real time and with high-resolution by labeling the constructs with fluorophores. Then, the concentration and schedule of siRNA-AuNP dosing will be systematically adjusted to find the regimen that is most effective at silencing glioblastoma genes, thereby producing the longest survival time. Finally, the effect of silencing multiple glioblastoma genes using a single platform will be studied by coating the gold nanoparticles with multiple siRNA sequences. This should yield a synergistic improvement in tumor regression and overall survival. Successful completion of these aims will render siRNA-AuNPs a unique, minimally invasive, safe, and effective alternative to conventional therapy for glioblastoma. This work will not only validate the use of siRNA-AuNPs for treatment of glioblastoma, but also provide insight into the effects of RNAi in vivo. The long-term goals of this project are to transition this novel therapy into clinical trials for glioblastoma and to expand this application o other types of neoplasia.
There is a significant need for improvements in care of glioblastoma patients not only to improve survival but also to improve quality of life post treatment. This research will develop a new therapy to meet this need that may be extended to other cancers and diseases in the future as well, substantially impacting public health.
| Kouri, Fotini M; Hurley, Lisa A; Daniel, Weston L et al. (2015) miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev 29:732-45 |
| Jensen, Samuel A; Day, Emily S; Ko, Caroline H et al. (2013) Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci Transl Med 5:209ra152 |
