A multifunctional nanomaterial platform for reducing morbidity in medulloblastoma therapy - Medulloblastoma (MB) is a malignant pediatric primary brain tumor and leading cause of cancer-related deaths in children. Surgical resection is the first line of treatment and aims to limit damage to surrounding healthy tissue to preserve normal function while removing as much of the tumor as possible. Typically, chemoradiotherapy (CRT) is applied after surgery to eliminate residual disease, where the tumor bed is first irradiated with high- energy radiation, followed by multidrug chemotherapy. While this aggressive CRT approach has improved five- year survival rates to ~70%, the tradeoff is serious morbidities, including irreversible neurologic and intellectual damage and the development of secondary malignancies, which reduce the overall quality of life and future academic success of MB survivors. Therefore, new methods for safer therapy of MB are still needed to reduce morbidity and improve the quality of life of MB survivors. To address this need, we will utilize a self-assembled nanomaterial platform (SAE) with cancer-specific accumulation that our group has recently developed. Specifically, SAE is a short self-assembling peptide conjugated with Indocyanine Green (ICG) and a Gadolinium (Gd) complex for near-infrared (NIR) fluorescence and MRI contrast, respectively. In addition, this multifunctional nanomaterial platform locally generates toxic levels of reactive oxygen species (ROS) when activated using low- intensity ultrasound (i.e., sonodynamic therapy, SDT). In the preliminary experiments, we showed that SAE strongly accumulated in a rat glioblastoma (GBM) model with ~70% cancer cell positivity and extended retention time (>7 days) through LDL-receptor-mediated transcytosis and uptake. Based on these strong preliminary data, we hypothesize that SAE can be transported across the blood-brain barrier (BBB) and accumulate in MB tumors. Upon MB-specific accumulation, this multifunctional nanomaterial will enable MRI diagnosis of MB tumors and pre-operative planning, NIR fluorescence image-guided surgery, intraoperative MRI to ensure maximal tumor resection, and intraoperative SDT to eliminate residual disease. Importantly, this broad functionality will be achieved using a simple, biocompatible peptide conjugated with two FDA-approved contrast agents (ICG and Gd), which will work synergistically to achieve these functions. In the preclinical studies proposed here, we will validate this multifunctional nanomaterial platform in the detection and therapy of MB tumors. In addition, BBB crossing and cancer cell internalization mechanisms, pharmacokinetics, biodistribution, and toxicity of SAE will be studied using various in vitro and in vivo models. The successful completion of these preclinical studies will generate strong preliminary data for further evaluation of this multifunctional nanomaterial platform in more detailed in vivo studies and early-phase clinical trials, which will be pursued in future R01 submissions. Translating this technology to the clinic would be transformative in managing MB by significantly reducing morbidities associated with surgery and CRT of MB tumors.
