Nanotherapeutic enhancement of interstitial thermal therapy for glioblastoma

胶质母细胞瘤间质热疗法的纳米治疗增强

基本信息

批准号：
10583661
负责人：
Huang Chiao Huang
金额：
$ 64.84万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583661
关键词：
Ablation Acceleration Adhesives Adverse effects Adverse event Antibodies Binding Biology Blood - brain barrier anatomy Brain Brain Edema Brain Injuries Brain Neoplasms Bypass Cell Death Cells Clinical Clinical Research Clinical Trials Combined Modality Therapy Complex Development Disease Disease Management Drug Delivery Systems Electric Capacitance Fibroblast Growth Factor Formulation Glioblastoma Heating Human Immunologic Deficiency Syndromes Implant In Vitro Invaded Knowledge Lasers Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Modeling Monitor Nanotechnology Normal tissue morphology Operative Surgical Procedures Patients Penetration Polyethylene Glycols Publishing Radiation Radiation therapy Radiosensitization Rat Transgene Rattus Recurrent tumor Resistance Robotics Rodent Safety Seizures Solid Neoplasm Technology Temperature Testing Thermal Ablation Therapy Thermometry Time Treatment Protocols Tumor Necrosis Factor Receptor Tumor Tissue Unresectable X-Ray Computed Tomography brain tissue cancer cell chemotherapy clinical efficacy clinical translation efficacy evaluation experience image guided improved in silico in vivo interstitial local drug delivery member minimally invasive multidisciplinary nanoGold nanoparticle nanotherapeutic neuro-oncology neurosurgery novel novel strategies patient derived xenograft model phase I trial photothermal therapy plasmonics preclinical efficacy preclinical safety receptor response side effect spatiotemporal therapy resistant tool translational approach treatment strategy tumor virtual

项目摘要

Project Summary Brain invasion, limited drug delivery, and treatment resistance render glioblastoma (GBM) virtually untreatable with current surgical, chemo- and radiation therapy approaches. Tumor recurrence is nearly universal, and the median patient survival (~15 months) has not changed significantly in 20 years. Radical new ideas and approaches are needed to change the course of this devastating disease. New neurosurgical approaches to treating GBM are emerging with the FDA approval of minimally invasive and image-guided technologies that now enable access to and treatment of previously unresectable and complex recurrent tumors. A major advance has been the development of magnetic resonance imaging (MRI)-guided and monitored, robotically controlled laser probes for intra-tumoral thermal treatments (e.g., laser interstitial thermal therapy [LITT]). LITT is increasingly used to treat deep-seated, unresectable tumors through both direct thermal ablation and priming to sensitize the tumor to radiation. Such thermal priming of solid tumors, including GBM, has been known for decades to increase the efficacy of radiation treatment. However, tools to safely and effectively accomplish this in neurosurgery have been lacking. Our clinical research team is leading two Phase I trials (NCT04181684, NCT04699773) investigating LITT-based priming of GBM for enhanced radiation. While the preliminary results in GBM patients have been promising, many patients (~40%) experience usually temporary adverse effects, such as brain edema and seizures. We predict that improving the heat transfer within the tumor and reducing thermal effects on surrounding brain tissues will reduce side effects and accelerate the clinical translation and efficacy of this new approach. Gold nanoparticle (AuNP)-enhanced photothermal ablation can increase thermal conductance and capacitance within the tumor and reduce heat transfer to surrounding normal tissues. Combining AuNPs and LITT offers the opportunity to improve the efficacy and safety of LITT. Our multidisciplinary team of experts in surgical neuro-oncology (Woodworth), DART nanotechnology (Kim), GBM Fn14 biology (Winkles), and plasmonic nanoparticles for photothermal therapy (Huang), is developing an advanced local drug delivery strategy that bypasses the blood-brain barrier and leverages a novel Decreased nonspecific-Adhesivity, Receptor-Targeted (DART) NP formulation. We have shown that DART nanoparticles, targeted to the tumor necrosis factor receptor superfamily member fibroblast growth factor-inducible 14 (Fn14), can penetrate tumor tissues to provide more uniform dispersion and selectively bind to and enter GBM cells, including those in the invasive margin. The central hypothesis is that controlled, monitored intratumoral delivery of Fn14-targeted DART AuNPs will significantly enhance LITT for GBM with fewer side effects on surrounding brain tissues. We will test this hypothesis in Fn14+ or Fn14- GBM patient-derived xenograft (PDX) models using immunodeficient rats and in an RCAS/tv-a-based transgenic rat model of Fn14+ human GBM.

项目概要脑部侵袭、有限的药物输送和治疗耐药性使得胶质母细胞瘤 (GBM) 几乎无法治疗目前的手术、化疗和放射治疗方法。肿瘤复发几乎是普遍的，而且 20 年来，患者中位生存期（约 15 个月）没有显着变化。激进的新想法和需要采取一些措施来改变这种毁灭性疾病的病程。随着 FDA 批准微创治疗 GBM 的新神经外科方法正在出现和图像引导技术，现在可以访问和治疗以前无法切除的复杂疾病复发性肿瘤。一项重大进展是磁共振成像（MRI）引导和用于肿瘤内热处理的受监控、机器人控制的激光探头（例如，激光间质热治疗）疗法[LITT]）。 LITT 越来越多地用于通过直接热疗法治疗深部不可切除的肿瘤消融和启动以使肿瘤对辐射敏感。这种实体瘤的热启动，包括 GBM，几十年来，人们已经知道它可以提高放射治疗的功效。然而，工具可以安全地、神经外科领域一直缺乏有效地实现这一目标。我们的临床研究团队正在领导两个阶段 I 试验（NCT04181684、NCT04699773）研究基于 LITT 的 GBM 启动以增强辐射。尽管 GBM 患者的初步结果是有希望的，许多患者 (~40%) 通常会经历暂时的不良反应，例如脑水肿和癫痫发作。我们预测，改善内部的传热肿瘤和减少对周围脑组织的热效应将减少副作用并加速这种新方法的临床转化和功效。金纳米粒子（AuNP）增强光热烧蚀可以增加热导率和肿瘤内的电容并减少向周围正常组织的热传递。结合 AuNP 和 LITT 提供了提高 LITT 有效性和安全性的机会。我们的多学科专家团队外科神经肿瘤学 (Woodworth)、DART 纳米技术 (Kim)、GBM Fn14 生物学 (Winkles) 和用于光热疗法的等离子体纳米颗粒（Huang）正在开发一种先进的局部药物输送绕过血脑屏障并利用新型降低非特异性粘附性的策略，受体靶向 (DART) NP 配方。我们已经证明 DART 纳米粒子能够靶向肿瘤坏死因子受体超家族成员成纤维细胞生长因子诱导型 14 (Fn14)，可穿透肿瘤组织提供更均匀的分散并选择性地结合并进入 GBM 细胞，包括位于侵入边缘。中心假设是受控、监测的 Fn14 靶向肿瘤内递送 DART AuNPs 将显着增强 GBM 的 LITT，同时对周围脑组织的副作用更少。我们将使用免疫缺陷在 Fn14+ 或 Fn14- GBM 患者来源的异种移植 (PDX) 模型中检验这一假设大鼠和基于 RCAS/tv-a 的 Fn14+ 人 GBM 转基因大鼠模型。