Glioblastoma multiforme (GBM) is both the most common and most lethal primary malignant brain tumor in adults. Patients with GBM have a mean survival of 15 months or less, despite current therapy (surgery, chemotherapy, and radiation). Surgery is a mainstay of GBM treatment and the extent of tumor resection has been shown to correlate with patient survival. However, complete GBM resections are usually not possible because of the inability to visualize the full extent of the infiltrating tumor, and becaue wide margin resections are prohibitive in the brain. Tumor cells migrate through the normal brain parenchyma and a clear delineation of the tumor margins is not always possible. Infiltrating tumor cells extend beyond what is usually depicted with contrast-enhanced MRI, and cannot be seen with the unaided eye during surgery. An imaging method sensitive enough to detect residual tumor cells during the operative procedure could guide neurosurgeons to perform more complete resections and improve survival. The overall goal of this project is to develop a novel approach to brain tumor management that allows preoperative staging, intraoperative 3D high-resolution imaging and photothermal ablation of GBMs using a single nanoprobe. We propose to accomplish this with a novel theranostic triple-modality MRI-Photoacoustic- Raman nanoparticle (MPR-Nanostars). MPR-Nanostars can be detected with these three modalities, and each has unique complementary strengths. This enables preoperative staging with MRI, 3D real-time bulk tumor visualization with Photoacoustic Imaging, and ultrahigh sensitivity detection of small tumor clusters with Raman imaging. Because of the stable retention of MPR-Nanostars within the tumor, pre- and intraoperative imaging can be performed with a single intravenous injection. We will first optimize the MPR-Nanostars to further improve their tumor targeting properties. Next we will characterize the behavior of the nanoparticles in vivo. Here we will use non-invasive dynamic positron emission tomography imaging and conventional methods to quantify biodistribution, and will perform detailed toxicity studies. We will then assess the accuracy of delineating GBMs by nanoparticle-MRI preoperatively and by nanoparticle-Photoacoustic Imaging and -Raman imaging intraoperatively. This will be followed by the optimization of the MPR-Nanostar's ability to destroy microscopic residual tumor via photothermal ablation. All in vivo experiments will be performed in two different GBM mouse models that closely recapitulate human disease. Because the MPR-Nanostars are made of inert gold and silica uniquely built around an FDA-approved iron oxide nanoparticle core, this theranostic nanotechnology approach has a significant potential for clinical translation. The results obtained from this proposal could significantly accelerate the translation of this novel strategy into the clinic, and ultimately lead to improved survival of brain tumor patients.
The proposed research aims at developing a novel triple-modality nanoparticle approach for combined preoperative and intraoperative brain tumor visualization and treatment. It harnesses the complimentary strengths of Magnetic Resonance Imaging, Photoacoustic Imaging and Raman Imaging to allow both deep tissue imaging and ultrahigh sensitivity detection of glioblastomas. This novel theranostic approach has the potential to significantly improve the clinical outcome of glioblastoma patients, by combining optimal preoperative staging with more accurate image-guided resection and the ability to destroy unresectable tumor via photothermal ablation.
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