Abstract
Simple SummaryGlioblastoma (GBM) is the most common form of brain cancer and among the most lethal of human cancers. Radiation therapy is a mainstay in the standard of care for GBM, killing tumor cells by creating DNA damage. Inhibiting DNA damage repair (DDR) proteins enhances radiation therapy by not allowing tumor cells to repair the DNA damage caused by radiation. The aim of our study was to investigate whether the novel nanoparticle material, ECO, could be used to deliver small interfering RNA (siRNA) to GBM tumor cells and temporarily reduce the production of DDR proteins to improve radiation therapy outcomes. SiRNAs can be designed to target an innumerable number of genes and with the right delivery vehicle can be used in a variety of disease settings. Our work provides support for the use of the novel ECO material for delivery of siRNA in GBM.Radiation therapy is a mainstay in the standard of care for glioblastoma (GBM), thus inhibiting the DNA damage response (DDR) is a major strategy to improve radiation response and therapeutic outcomes. Small interfering RNA (siRNA) therapy holds immeasurable potential for the treatment of GBM, however delivery of the siRNA payload remains the largest obstacle for clinical implementation. Here we demonstrate the effectiveness of the novel nanomaterial, ECO (1-aminoethylimino[bis(N-oleoylcysteinylaminoethyl) propionamide]), to deliver siRNA targeting DDR proteins ataxia telangiectasia mutated and DNA-dependent protein kinase (DNApk-cs) for the radiosensitzation of GBM in vitro and in vivo. ECO nanoparticles (NPs) were shown to efficiently deliver siRNA and silence target protein expression in glioma (U251) and glioma stem cell lines (NSC11, GBMJ1). Importantly, ECO NPs displayed no cytotoxicity and minimal silencing of genes in normal astrocytes. Treatment with ECO/siRNA NPs and radiation resulted in the prolonged presence of γH2AX foci, indicators of DNA damage, and increased radiosensitivity in all tumor cell lines. In vivo, intratumoral injection of ECO/siDNApk-cs NPs with radiation resulted in a significant increase in survival compared with injection of NPs alone. These data suggest the ECO nanomaterial can effectively deliver siRNA to more selectively target and radiosensitize tumor cells to improve therapeutic outcomes in GBM.
Highlights
Glioblastoma (GBM) is the most common and lethal primary brain tumor
We first investigated the cytotoxicity of unlabeled (E) and RGD-polyethylene glycol (PEG) (R) labeled ECO nanoparticles (NPs) on normal astrocytes (NAs), glioblastoma (GBM) tumor cells, and glioma stem-like cells (GSCs) using an ATP-based cell viability assay (Figure 1)
Targeting multiple pathways always carries the potential for additional toxicity, our study showed that while the combination Small interfering RNA (siRNA) treatment significantly inhibited the repair of radiation-induced DNA damage in all tumor cell lines tested, normal astrocytes showed no significant difference in DNA damage repair for any siRNA treatment delivered
Summary
Despite advances in precision medicine and targeted therapies, the standard of care for GBM continues to be surgical resection followed by concomitant radiation and temozolomide. With this treatment regimen the overall survival for patients with GBM is a sobering ~14 months with a 5-year survival of ~5% [1,2]. Drugs blocking ATM and DNApk have shown to radiosensitize GBM cells in preclinical settings, but those successes have yet to translate into the clinic [6,7,8]. Major obstacles to the use of these drugs include off-target effects and toxicity that limit the ability to deliver doses across the blood brain barrier that produce sufficient radiosensitization for increases in overall survival [7,9]
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