Convection-enhanced Delivery of Radiosensitizer-Encapsulating Nanoparticles for the Treatment of Pediatric Brainstem Gliomas

 描述(由申请人提供)：尽管在过去的几十年里进行了无数的临床试验，但弥漫性桥脑胶质瘤(DIPG)的儿科患者的预后仍然严峻。目前，只有一种有效的治疗方法可以提高DIPG患者的中位生存期：分割放射治疗(FRT)。为了克服DIPG治疗进展的平台期，提出了一种新的、多模式的治疗方法，该方法充分利用了FRT在改善预后方面的潜力，并解决了与当前DIPG临床试验相关的两个主要问题。首先，系统传递的药物对DIPG肿瘤的渗透受到高度保护的血脑屏障(BBB)的严重限制。其次，许多系统疗法在DIPG中是通过从成人高级别胶质瘤试验中推断出来的，没有明确的理由将这些疗法在两组遗传不同的肿瘤之间转换。为了同时克服这些问题，该项目建议使用DIPG验证的放射增敏剂--这将增强FRT对DIPG细胞的影响--与对流增强输送(CED)系统相结合，该系统将绕过血脑屏障，允许治疗药物直接输送到肿瘤。放射增敏剂将被包裹在聚合物纳米颗粒(NP)中，这些纳米颗粒在进入肿瘤后会慢慢降解。这种缓慢的降解在肿瘤中提供了持续的药物水平，使得在接受FRT期间和FRT后长达两周的恢复期都可以进行有效的放射增敏。这个项目是基于这样的假设，即FRT和CED的结合将抑制FRT诱导的双链DNA断裂后的DNA修复，从而减少肿瘤复发，并最终提高患者的总存活率。为了验证这一假设，该项目被分为三个具体目标。第一个目标是在细胞培养模型中制作和测试负载放射增敏剂的NP对细胞DNA修复和dsDNA断裂后存活的影响。第二个目的是将这些纳米粒子用于啮齿动物颅内肿瘤模型，以优化其均匀穿透和滞留在肿瘤内的能力。最后，第三个目标是测试和优化这种方法的治疗效果，方法是将AIMS 1和AIMS 2中针对抑制DNA修复以及颅内肿瘤中的均匀分布和滞留而优化的装载放射增敏剂的NPs与DIPG啮齿动物模型的FRT相结合。这些拟议目标的完成将证明一种新的多模式方法的可行性，以治疗一种在过去30年中没有看到预后改善的毁灭性的儿科疾病。此外，该项目将为CED递送装载放射增敏剂的纳米粒子以在FRT期间进行持续放射增敏的新组合建立先例，该组合可应用于其他脑肿瘤和脊柱肿瘤。

 DESCRIPTION (provided by applicant): Despite numerous clinical trials over the past several decades, the prognosis for pediatric patients with diffuse intrinsic pontine glioma (DIPG) remains grim. Currently, there is only one validated treatment for improving median survival of patients with DIPG: fractionated radiation therapy (FRT). To overcome the plateau in treatment advancement for DIPG, a novel, multi-modal approach to therapy is proposed that capitalizes on the al- ready proven potential of FRT for prognostic improvement and addresses two major issues associated with current clinical trials for DIPG. First, systemically-delivered drug penetration into DIPG tumors is severely limited by the highly-protective blood brain barrier (BBB). Second, many systemic therapies have been tested in DIPG by extrapolation from adult high grade glioma trials, without clear rationale for the translation of these therapies between two genetically distinct groups of tumors. To simultaneously overcome these issues, this project proposes to use DIPG-validated radiosensitizing agents - which will enhance the effects of FRT on DIPG cells - combined with a convection enhanced delivery (CED) system, which will bypass the BBB and al- low delivery of therapeutics directly to the tumor. Radiosensitizers will be encapsulated in polymeric nanoparticles (NP), which will slowly degrade after delivery into the tumor. This slow degradation provides sustained levels of drug in the tumor which allow effective radiosensitization during both the administration of FRT and the post-FRT recovery period of up to two weeks. This project is based on the hypothesis that the combination of FRT with CED of radiosensitizer-loaded NPs will inhibit DNA repair following FRT-induced dsDNA breaks, thus decreasing tumor recurrence and ultimately increasing overall patient survival. To test this hypothesis the project is divided into the three specific aims. The first aim focuses on the fabrication and testing of radiosensitizer-loaded NP in cell culture models for their effects o cellular DNA repair and survival following dsDNA breaks. The second aim focuses on CED of these NPs to rodent models of intracranial tumors in order to optimize their ability to homogeneously penetrate and be retained within the tumor. Finally, the third aim focuses on testing and optimizing the therapeutic efficacy of this approach by combining radiosensitizer-loaded NPs - optimized in aims 1 and 2 for inhibition of DNA repair and homogenous distribution and retention in intracranial tumors - with FRT in rodent models of DIPG. Completion of these proposed aims will demonstrate the feasibility of a new multi-modal approach to treatment of a devastating pediatric disease that has not seen prognostic improvement over the past 30 years. Additionally, this project will establish a precedent for the novel combination of CED delivery of radiosensitizer-loaded NPs for sustained radiosensitization during FRT that can be applied to other tumors of the brain and spine.