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Nanoparticle-Based Triple Modality Imaging and Photothermal Therapy of Brain Tumors

基于纳米颗粒的脑肿瘤三模态成像和光热疗法

基本信息

批准号：
9092358
负责人：
SANJIV S GAMBHIR
金额：
$ 35.95万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9092358
关键词：
ADME Study Address Animal Model Animals Beds Biodistribution Blood - brain barrier anatomy Brain Brain Neoplasms Canis familiaris Chemistry Clinical Clinical Management Detection Devices Diagnostic Imaging Dose Ensure Excision Excretory function Formulation Gadolinium Glioblastoma Glioma Goals Gold Growth Housing Human Image Imagery Injection of therapeutic agent Ions Lead Magnetic Resonance Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measures Metabolism Microscopic Modality Modeling Mus Nanotechnology Operating Rooms Operative Surgical Procedures Outcome Ovarian Pancreas Patients Physiology Primary Brain Neoplasms Production Prostate Quality of life Radiation therapy Residual Tumors Residual state Resistance Resolution Sensitivity and Specificity Shapes Signal Transduction Silicon Dioxide Solid Neoplasm Specificity Staging Surgical Management Therapeutic Time Toxic effect Transgenic Mice Translations Tumor Burden Tumor Tissue Visual Weight Work absorption arm base biological systems brain tissue brain tumor resection cancer imaging cell type chemotherapy gadolinium oxide image guided therapy imaging agent imaging modality improved in vivo intravenous injection miniaturize molecular imaging mouse model nanoparticle nanorod neoplastic cell novel photoacoustic imaging public health relevance quantitative imaging retinal rods small molecule standard of care technique development theranostics tool tumor tumor ablation uptake

项目摘要

DESCRIPTION (provided by applicant): 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.