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

• 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
• 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

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.

项目摘要 脑部入侵，有限的药物输送和耐药性使胶质母细胞瘤（GBM）几乎无法治疗 采用目前的手术，化学和放射治疗方法。肿瘤复发几乎是普遍的， 中位患者生存（约15个月）在20年内没有发生显着变化。激进的新想法和 需要采取方法来改变这种毁灭性疾病的过程。 FDA批准最低限度侵入性，正在出现新的神经外科手术方法 以及图像指导的技术，现在可以访问和处理以前无法切除和复杂的技术 复发性肿瘤。主要进步是磁共振成像（MRI）指导的发展 受监测的，机器人控制的激光探针，用于肿瘤内热处理（例如，激光间隙热治疗 治疗[LITT]）。 LITT越来越多地用于治疗通过两种直接热的深处，无法切除的肿瘤 消融和启动以使肿瘤敏感到辐射。这些实体瘤的热启动，包括GBM， 数十年来一直闻名，以提高辐射治疗的功效。但是，可以安全的工具 在神经外科手术中有效地实现了这一点。我们的临床研究团队正在领导两个阶段 I试验（NCT04181684，NCT04699773）研究了基于LITT的GBM启动，以增强辐射。尽管 GBM患者的初步结果很有希望，许多患者（约40％）通常 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影响将减少副作用并加速 这种新方法的临床翻译和功效。 金纳米颗粒（AUNP）增强光热消融可以增加导热电导率和 肿瘤内的电容，并减少热传递到周围正常组织。结合Aunps和 Litt提供了提高LITT功效和安全性的机会。我们的多学科专家团队 手术神经肿瘤学（Woodworth），DART纳米技术（KIM），GBM FN14生物学（Winkles）和 血浆纳米颗粒用于光热疗法（Huang），正在开发先进的局部药物输送 绕过血脑屏障并利用新颖的策略降低了非特异性粘附性， 受体靶向（DART）NP公式。我们已经表明，针对肿瘤的飞镖纳米颗粒 坏死因子受体超家族成员成纤维细胞生长因子诱导14（FN14）可以穿透肿瘤 组织以提供更均匀的色散并选择性地结合并进入GBM细胞，包括 侵入性边缘。中心假设是受控的，受监测的FN14靶向的肿瘤内递送 DART AUNPS将显着增强GBM的LITT，对周围脑组织的副作用较少。我们 将在FN14+或FN14- GBM患者衍生的异种移植（PDX）模型中检验该假设 大鼠和基于RCAS/TV-A的FN14+人GBM的转基因大鼠模型。