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

基于纳米粒子的脑肿瘤三模态成像和光热疗法

基本信息

批准号：
9766199
负责人：
SANJIV S GAMBHIR
金额：
$ 34.88万
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/9766199
关键词：
Address Animal Model Animals Beds Biodistribution Blood - brain barrier anatomy Brain Brain Neoplasms Brain imaging Canis familiaris Chemistry Clinical Clinical Management Detection Devices Diagnostic Imaging Dimensions Dose Ensure Excision Excretory function Formulation Gadolinium Glioblastoma Glioma Goals Gold Growth Human Image Imagery Injections Intravenous 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 Tumor Burden Tumor Tissue Visual Work absorption base biological systems brain shape brain tissue brain tumor resection cancer imaging cell type chemotherapy clinical translation high resolution imaging human model image guided therapy imaging agent imaging modality improved in vivo intravenous injection miniaturize molecular imaging mouse model nanoparticle nanorod novel photoacoustic imaging photothermal therapy 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.

描述（由申请人提供）：恶性原发性脑肿瘤特别是多形性胶质母细胞瘤（神经胶质瘤或 GBM）的临床和手术治疗是一个主要的治疗挑战。其原因有两个：1）手术切除不能去除所有高度浸润的肿瘤。 2) GBM 对放疗和化疗有抵抗力，因此肿瘤经常复发，中位生存期仅为 9-15 个月。该项目的重点是一种新颖的双臂 GBM 治疗方法，涉及使用单一药物进行术前分期和术中高分辨率成像，该成像剂将提供光热治疗以进一步消融任何疾病。我们将通过我们实验室最近开发的新型三模态 MRI-光声-拉曼纳米颗粒 (MPRN) 来实现这一目标。这种超高灵敏度 (pM) 纳米颗粒由拉曼活性小颗粒组成。分子层吸附在惰性金核上，并由二氧化硅壳保护，该壳随后涂有钆离子，用于 T1 加权 MRI 信号。 GBM小鼠模型中的光声学和拉曼成像高分辨率引导肿瘤切除由于纳米颗粒被脑肿瘤保留超过一周，因此它可以对脑肿瘤进行成像。我们现在建议在术前和术中单次静脉注射纳米颗粒，进一步提高 MPRN 的敏感性，优化形状和尺寸，简化化学和生产，并表征其在动物模型中的临床应用。然后，我们将使用 MPRN 来评估脑肿瘤描绘的准确性。术前 MRI 以及术中拉曼和 PAI 的浸润性肿瘤边缘我们还将研究使用光热肿瘤消融同时成像和治疗的可行性，这种治疗对于消除由于与肿瘤融合而无法切除的肿瘤病灶尤其重要。对于这些体内研究，我们将使用与人类神经胶质瘤生长密切相关的自发犬病例和转基因小鼠脑肿瘤模型，因为此处使用的 MPRN 方法基于金和二氧化硅。由于纳米颗粒相对惰性，并且已经在某些配方中进入人体试验，因此我们的方法具有巨大的临床转化潜力。此外，可在手术室使用的小型化拉曼和光声设备已经在内部和商业上开发出来。这里提出的改进可以显着加速临床转化，我们希望这种方法最终不仅能改善 GBM 切除和治疗，还能应用于包括前列腺和卵巢在内的许多实体瘤。