Clinical and surgical management of malignant primary brain tumors particularly glioblastoma multiforme (glioma or GBM) is a major therapeutic challenge. The reasons for this are two-fold: 1) surgical resection cannot remove all of the highly infiltrative tumor mass, and 2) GBM is resistant to radiotherapy and chemotherapy. As a result, the tumor frequently recurs, and the median survival is a dismal 9-15 months. The overall goal of this project is a novel two-armed approach to GBM treatment involving both imaging-guided therapy. Using a single agent, we will provide both preoperative staging and intraoperative high-resolution imaging. This same imaging agent will offer photothermal therapy to further ablate any residual tumor mass. We will accomplish this with a novel triple-modality MRI-Photoacoustic-Raman nanoparticle (MPRN) recently developed in our lab. This ultra-high sensitivity (pM) nanoparticle consists of a Raman active small molecule layer adsorbed on an inert gold core and protected by a silica shell. This shell is subsequently coated with gadolinium ions for T1-weighted MRI signal. We have used this tool for three-dimensional visualization of brain tumors with MRI, deep tumor visualization with photoacoustics, and high-resolution guidance of tumor resection with Raman imaging in a mouse model of GBM. Because the nanoparticle is retained by the brain tumor for more than a week, it allows imaging of the brain tumor both preoperatively and intraoperatively with a single intravenous injection of the nanoparticle. We now propose to further improve MPRN sensitivity, optimize shape and size, simplify chemistry and production, and characterize its clinical utility in animal models. We will also investigate the whole-body and tumor biodistribution of the nanoparticle, and perform detailed Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) studies. We will then use the MPRN to assess the accuracy of delineation of brain tumors by MRI pre-operatively as well as invasive tumor margins by intraoperative Raman and PAI. We will also investigate the feasibility of simultaneous imaging and therapy using photothermal tumor ablation. Such therapy is especially critical to eliminate tumor foci that cannot be removed due to their integration with normal brain tissue. For these in vivo studies, we will use spontaneous canine cases and transgenic mouse brain tumor models that closely mimic the growth of human gliomas. Because the MPRN approach used here is based on gold and silica-based nanoparticles that are relatively inert and have already entered human trials in certain formulations, our approach has significant potential for clinical translation. In addition, miniaturized Raman and photoacoustic devices that could be used in the operating room have already been developed both in house and commercially, and the improvements proposed here could significantly accelerate clinical translation. We hope that this approach will ultimately lea to not only to improved GBM resection and treatment, but also find applications to many solid tumors including prostate and ovarian.

Public Health Relevance

Brain cancers such as glioblastoma multiforme are particularly aggressive cancers that respond poorly to the current treatments of surgery, chemotherapy, and radiotherapy. This work proposes to solve this challenge with a nanoparticle agent that deliver magnetic resonance imaging, photoacoustic imaging, and Raman imaging as well as photothermal therapy to ablate the tumor. Sensitive and selective removal of tumor is possible because the nanoparticles only accumulate in the tumor tissue, and we envision that this approach may have utility with many other tumor types including ovarian, prostate, and pancreatic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Grodzinski, Piotr
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Stanford University
Schools of Medicine
United States
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Weissleder, Ralph; Schwaiger, Markus C; Gambhir, Sanjiv Sam et al. (2016) Imaging approaches to optimize molecular therapies. Sci Transl Med 8:355ps16
Thakor, Avnesh S; Jokerst, Jesse V; Ghanouni, Pejman et al. (2016) Clinically Approved Nanoparticle Imaging Agents. J Nucl Med 57:1833-1837