Malignant brain tumors remain a therapeutic challenge, partially because of the difficulty of visualizing the tumor borders during surgical resection. The overall goal of this project is to develop a new molecular approach to brain tumor imaging that allows both preoperative staging and intraoperative high-resolution imaging using a single injectable contrast agent. We propose to accomplish this by using a novel dual-modality MRI-Raman nanoparticle. This nanoparticle consists of a thin Raman active layer adsorbed to an inert gold core (increasing the Raman signal ~1014-fold) protected by a silica shell, and is coated with gadolinium ions. This nanoparticle can be detected by both MRI and Raman spectroscopic imaging with very high sensitivity. It was shown that this nanoparticle allows three-dimensional visualization of brain tumors with MRI, and high-resolution guidance of tumor resection with Raman imaging in a mouse glioblastoma model. Because the nanoparticle is retained by the brain tumor for more than a week, it allows performing both preoperative and intraoperative imaging with a single intravenous injection of the nanoparticle. We propose to initially further improve nanoparticle detectability and simplify its chemistry and production. We will also investigate the whole-body and tumor biodistribution of the nanoparticle, and perform detailed toxicity studies. We will then assess the accuracy of delineating brain tumors by nanoparticle-MRI preoperatively and delineating the invasive margin of brain tumors by intraoperative nanoparticle-Raman imaging. For these in vivo studies, we will use a transgenic mouse brain tumor model that closely mimics the growth of human gliomas. The nanoparticle approach used here has a significant potential for clinical translation as gold- silica nanoparticles are relatively inert materials and some of these constructs have already entered clinical trials. In addition, hand-held Raman imaging devices that could be used in the operating room have already been developed. The results obtained from this proposal could significantly accelerate the translation of this novel strategy into the clinics. We hope that this approach will ultimately lead to improved brain tumor resection and thus lead to better survival of brain tumor patients.
The proposed research aims at developing a novel dual-modality nanoparticle approach for combined preoperative and intraoperative brain tumor visualization. It harnesses the complementary strengths of magnetic resonance imaging (MRI) and Raman spectroscopy to allow both deep tissue imaging and ultra-high sensitivity detection of brain tumors. This novel combined imaging approach has clear clinical potential, in both the preoperative diagnosis of brain tumors and by providing better visualization of the tumor during surgical resection.
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