Image-guided combination therapies for radiotherapy-induced neurocognitive impairment in pediatric brain tumor survivors

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Approximately 90% of pediatric central nervous system tumor (CNST) survivors, treated with radiotherapy, experience radiotherapy-induced brain injury (RIBI) and neurocognitive decline later in life. This is a progressive treatment-related side effect, which impacts the quality of life of pediatric CNST survivors. Since more pediatric patients are surviving cancer, there is a growing need for RIBI prophylactic and therapeutic strategies. Chronic oxidative stress and neuroinflammation are key contributors to RIBI. Thus, neuroprotective strategies to reduce oxidative stress and neuroinflammation are being explored. Neuroengineering strategies using regenerative stem cells to repair RIBI are also being explored. However, prolonging the survival of transplanted stem cells at injury sites is a challenge, partly due to chronic oxidative stress and neuroinflammation. Accordingly, strategies to improve transplanted stem cell survival are on the horizon. For these strategies to be effective, drug delivery systems capable of effectively delivering neuroprotective drugs to brain injuries are greatly needed. Also critical for clinical translation efforts are methods to noninvasively image drug delivery and tissue responses to therapy. Nanotechnology in combination with image-guided neuro-interventional procedures are promising for drug delivery. In addition, diamagnetic chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) is a promising MRI technique that can be used to noninvasively and directly image organic drugs. Although, CEST MRI is based on a magnetic resonance spectroscopic (MRS) technique, it is more sensitive (~1000 times) than MRS. Furthermore, given the inherent correlation between CEST MRI signals, pH, and oxidative stress, it can also be used to image changes in tissue oxidative stress, in response to effective drug delivery. We propose to develop CEST MRI theranostic biosensors and complementary CEST MRI nanotheranostic agents for image- guided combination therapy of RIBI. In Aim 1, neuroprotective drugs will be screened by CEST MRI, and each drug’s potential to serve as a pH-dependent CEST MRI theranostic biosensor will be evaluated in our preclinical RIBI model. The feasibility of imaging changes in tissue oxidative stress in vivo with the CEST MRI theranostic agents will also be evaluated. In Aim 2, we will develop oxidative stress-activable CEST MRI nanotheranostic biosensors and evaluate each agent’s potential to sustainably reduce oxidative stress and neuroinflammation in our RIBI model. In Aim 3, we will evaluate the feasibility of improving transplanted stem cell survival and neurorepair in our RIBI model, by sustainably reducing oxidative stress and neuroinflammation. Stem cell survival will be imaged with our stem cell tracking MRI biosensor, capable of noninvasively imaging stem cell delivery, migration and survival. All results will be validated with multi-parametric MRI; PET imaging of neuroinflammation, using the translocator protein radiotracer [(11)C]DPA-713; behavioral tests of memory and learning; histology and immunohistochemistry. This project will advance the development of neuroprotective and neuroengineering strategies for RIBI in pediatric CNS survivors, ultimately improving their quality of life.