Enhancing the Efficacy of Cancer Radiation through ROS Generation by Nuclear Localizing Iron Oxide Nanoparticles

Mentors:  Anderson, Hilt

Iron oxide nanoparticles have the ability to enhance the production of reactive oxygen species (ROS) within cells through catalyzing the Haber-Weiss reaction (Fenton chemistry) which produces the hydroxyl radical. Cancer cells are more susceptible to oxidative insults compared to normal cells due to fast cell proliferation and metabolism so additional ROS stress induced by exogenous agents can overwhelm the relatively low antioxidant capacity and disrupt the redox homeostasis inside cancer cells leading to selective tumor cell toxicity. Iron oxide nanoparticles have been previously studied due to their multitude of biological applications, inherent biocompatibility, magnetic properties, and lack of protein adsorption after proper coating. Therefore, iron oxide nanoparticles coated with dextran will be used to improve the efficacy of radiation by enhancing the intracellular ROS production.

Due to the half-life of the hydroxyl radical being on the order of a nanosecond, the location of the production of the hydroxyl radical production is very important. If ROS can be generated at or within the nuclear envelope, the probability of interacting with the DNA and resulting in a double strand break increases. Therefore, the iron oxide nanoparticles will be conjugated with a Nuclear Localizing Signal (NLS) peptide. This signal has been shown to interact with cytosolic factors forming stable complexes that are docked at the nuclear pore complex (NPC) in the nuclear membrane. In order to target the nuclear envelope, it is important for the nanoparticle to escape the endosome after receptor-mediated or non-specific endocytosis. The NLS conjugated to the iron oxide nanoparticle surface must be able to interact with the cytoplasm in order to facilitate exiting the endosome.

As an undergraduate scholar, your contribution to this project with focus on developing an iron oxide nanoparticle conjugated with a NLS for localization of the nanoparticle at the nuclear envelope. The iron oxide nanoparticle can then catalyze the Haber-Weiss reaction through Fenton chemistry to enhance intracellular ROS generation with the expectation that this oxidative stress combined with radiation treatment will lead to synergistic treatment of lung cancer. This project will involve cell culture, confocal microscopy and nanoparticle characterization techniques