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

• 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
• 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

 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（胶质瘤或GBM）的临床和手术治疗是一个主要的治疗挑战。其原因有两个方面：1）手术切除不能去除所有高度浸润的肿瘤块，2）GBM对放疗和化疗有抗性。因此，肿瘤经常复发，中位生存期为9-15个月。该项目的总体目标是一种新的双臂GBM治疗方法，包括成像引导治疗。使用单一药物，我们将提供术前分期和术中高分辨率成像。这种相同的成像剂将提供光热治疗，以进一步消融任何残留的肿瘤块。我们将用我们实验室最近开发的一种新的三模态MRI-光声-拉曼纳米颗粒（MPRN）来实现这一点。这种超高灵敏度（pM）纳米颗粒由吸附在惰性金核上并由二氧化硅壳保护的拉曼活性小分子层组成。该外壳随后涂有钆离子，用于T1加权MRI信号。我们已经使用这个工具的三维可视化的脑肿瘤与MRI，深部肿瘤可视化与光声，和高分辨率的指导肿瘤切除与拉曼成像在小鼠模型GBM。因为纳米颗粒被脑肿瘤保留超过一周，所以它允许通过单次静脉注射纳米颗粒在术前和术中对脑肿瘤进行成像。我们现在建议进一步提高MPRN的敏感性，优化形状和大小，简化化学和生产，并表征其在动物模型中的临床实用性。我们还将研究纳米颗粒的全身和肿瘤生物分布，并进行详细的吸收，分布，代谢，排泄和毒性（ADME-Tox）研究。然后，我们将使用MPRN评估术前MRI描绘脑肿瘤的准确性以及术中拉曼和派描绘侵袭性肿瘤边缘的准确性。我们也将探讨同时使用光热肿瘤消融成像和治疗的可行性。这种治疗对于消除由于与正常脑组织整合而无法移除的肿瘤病灶尤其重要。对于这些体内研究，我们将使用自发的犬病例和转基因小鼠脑肿瘤模型，这些模型非常接近于模拟人类神经胶质瘤的生长。由于这里使用的MPRN方法是基于相对惰性的金和硅基纳米颗粒，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显著的临床转化潜力。此外，可以在手术室中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著加速临床转化。我们希望这种方法最终不仅能改善GBM的切除和治疗，而且还能应用于许多实体瘤，包括前列腺和卵巢。