Radiation therapy (radiotherapy) has been used to treat cancer for more than 100 years and new clinical innovations have allowed for very focused beams of radiation to kill malignant cells. These beams are made of high energy light particles that enter the body and cause water and oxygen to react and split into many different reactive oxygen species (ROS). These ROS then go on to destroy the genetic material inside a cell, which ultimately leads to the cell’s death. In cancer treatment, radiotherapy is usually not completely effective on its own. Sometimes it misses cancerous cells. Sometimes there’s not enough oxygen for it to create the therapeutic ROS. In fact, it is almost impossible to tell if it is working until a follow up appointment. Because radiation is composed of such high energy particles, not very many molecules directly interact with it; however, it is known that radiation kills cells because genetic material is so susceptible to chemical reactions with these ROS. It makes sense then that a molecular probe made from genetic material should be able to respond to radiation damage. This proposal focuses on designing new artificial biomaterial-based sensors that “look†almost exactly like the genetic material in your body except cells can’t read it like normal RNA or DNA and it won’t be degraded by enzymes in the body yet radiation affects it the exact same way. These new probes will be designed to target the mitochondria or the “powerhouse of the cell†to identify how radiation causes damage to cells. Finally, this work proposes to make a new type of nanomaterial that can glow when it is hit by radiation. One day, this sort of material might be able to tell doctors in real time if radiotherapy is working.
The overproduction of reactive oxygen species (ROS) damages genetic material, causing cell death. The causes of ROS overproduction are various and range from mitochondrial dysfunction to radiation exposure. Hydroxy radicals—reactive •OH—cannot be eliminated by enzymatic reactions and are uniquely powerful enough to induce single strand breaks in RNA and DNA. Understanding the chemistry of •OH is essential to address fundamental challenges in a number of arenas at the cellular and tissue levels. Several •OH sensitive fluorescent probes exist but they lack the sensitivity to detect the single digit μM concentrations in cells and/or cannot distinguish between •OH and other ROS. Thus, detecting or exploiting •OH—one of the most pernicious ROS—is hamstrung by a lack of adequate tools. The objective in this proposal is to optimize new L-RNA oligomers as a biorthogonal tool that can undergo strand scission “triggered†by •OH. The research team will show these optimized L-RNA can be synthetically tailored to target cellular organelles to report on •OH concentrations. Finally, L-RNA strand scission will be triggered as a nano-formulation in the presence of ROS to make a highly selective “smart†material. The central hypothesis is that L-RNA will undergo single strand cleavage at physiologically relevant •OH concentrations, is non-toxic, and will not be enzymatically destroyed in vitro or in vivo. At the conclusion of this proof-of-concept study, the expected outcome will be the validation of L-RNA as a long-lived and targetable sensor in vitro. The groundwork laid here will be further enabling in the development of new “biorthogonal†DNA and RNA architectures that can work in vivo and in vitro.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
