Nanotherapeutic enhancement of interstitial thermal therapy for glioblastoma

项目摘要 脑侵袭、有限的药物输送和治疗阻力使胶质母细胞瘤(GBM)几乎无法治疗 在目前的手术、化疗和放射治疗方法下。肿瘤复发几乎是普遍的，而且 患者的中位生存期(~15个月)在20年内没有明显变化。激进的新想法和 需要采取措施来改变这种毁灭性疾病的进程。 随着FDA批准微创治疗GBM，治疗GBM的新神经外科方法正在出现 以及图像引导技术，现在可以访问和治疗以前无法切除的复杂 复发性肿瘤。一个主要的进展是磁共振成像(MRI)引导和 用于肿瘤内热疗的受监控的、机器人控制的激光探头(例如，激光间质热疗 治疗[小])。LITT越来越多地被用于治疗深层次的、无法切除的肿瘤，通过直接热疗 消融和引爆以使肿瘤对辐射敏感。这种实体肿瘤的热启动，包括GBM， 几十年来，人们一直知道提高放射治疗的疗效。然而，用于安全和 在神经外科中有效地做到这一点一直是缺乏的。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增强辐射预置。而当 GBM患者的初步结果是有希望的，许多患者(~40%)通常经历 暂时的不良反应，如脑水肿和癫痫发作。我们预测，改善内部的热传递 肿瘤和降温对周围脑组织的影响会减少副作用，加速 这一新方法的临床翻译和疗效。 金纳米粒子(AuNP)增强的光热消融可以增加热导率和 肿瘤内的电容，并减少对周围正常组织的热传递。结合AuNPs和 LITT为提高LITT的疗效和安全性提供了机会。我们的多学科专家团队在 外科神经肿瘤学(Woodworth)，DART纳米技术(Kim)，GBM Fn14生物学(Winkles)，以及 用于光热治疗的等离子体纳米粒(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一种新的降低的非特异性粘附性的策略， 受体靶向(DART)NP制剂。我们已经证明了靶向肿瘤的DART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因子14(Fn14)，可穿透肿瘤 组织提供更均匀的分散，并选择性地结合和进入基底膜细胞，包括 侵袭性的边缘。中心假设是受控、监控的Fn14靶向肿瘤内递送 DART AuNPs可显著提高GBM的LITT，且对周围脑组织的副作用较小。我们 将在使用免疫缺陷的Fn14+或Fn14-GBM患者来源的异种移植(PDX)模型中测试这一假设 以RCAS/TV-a为基础的Fn14+人GBM转基因大鼠模型。

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.