Abstract
Despite significant advances in radiotherapy (RT) treatment modalities, highly radioresistant forms of cancer such as Glioblastoma Multiforme (GBM) remains a major clinical challenge due to poor prognostication. In the past decade, new forms of radiotherapy such as Nanoparticle-Mediated Radiation Therapy (NPRT) are under intense research as a new frontier for radiosensitization of highly resistant cancerous tumour. Nanoparticle Mediated Dose Enhancement of Radiation Therapy is emerging as a favourable modality for enhancing radiotherapeutic ratio through local tumour dose enhancement and radiosensitization. This is due to the ability of specific nanoparticles (NPs) to increase local physical dose deposition and subsequent, direct damage to cells and DNA within their local vicinity. High electron density and atomic number NPs act both as a radiosensitizers and radioenhancers with high radiation dose enhancement (DE) properties that enhances the local dose through the release of more secondary electrons, radiochemical yields through enhanced ROS generation in within the tumour volumes.
Optimizing the therapeutic efficacy of these nanoparticles rely on our current understanding of the underlying principles of NP radio-enhancement as it relates to the potential to release copious electrons into a nanoscale volume, thereby amplifying radiation-induced biological damage. In this work, we have successfully used high electron density, PEGylated (biocompatible) core-shell quantum dots (QDs) and carbon quantum dots to 1) amplify the local dose; 2) enhance the generation of ROS in vitro 3) assess the amount of ROS Generation and 3) to radiosensitize highly resistant cancer cell lines. The objective and motivation of our work are to enhance radiotherapy outcomes for glioblastoma through local dose enhancement and radiosensitization. By improving radiosensitization through increased ROS generation, we effectively lower the prescribed dose while maintaining the desired treatment outcome
Having recently published our novel assay wherein we used fluorescence intensity modulation of CdSe/ZnS quantum dots (QDs) to assess reactive oxygen species (ROS) generation during chemotherapy and radiotherapy for cancer cells, we are applying this assay for concurrent measurement of ROS and radiosensitization. Using a Faxitron Cell Irradiator, we irradiate brain cancer cells (T98G and U87 Glioblastoma cells) treated with QDs and measure both their migration and the QD fluorescence intensity. We measure and quantify the cell attachment, proliferation and migration using a commercially available Electric Cell Impedance Sensor (ECIS) method.
Irradiated T98G cells initially attached and migrated significantly (p<0.0001) more than non-irradiated cells in the first 20 hours post-irradiation and showed significant cell death thereafter. By calculating the fluorescence intensity ratio (FIR), we demonstrated that our approach results to enhanced ROD generation by almost a factor of 2 for 20Gy compared to 5Gy for PEG CdSe/ZnS QDs. Carbon quantum dots showed a significant fluorescence enhancement. Its ECIS analysis did not show any significant cell migration, as most of the cells died either during and immediately after IR. Increased ROS generation is due to higher radiochemical yields resulting from local dose amplification. Hence, functionalized nanoparticles such as PEG CdSe/ZnS QDs provide a novel alternative for the treatment of highly resistant brains tumours.