CED of Nanoparticles Loading with Novel Agents for Improved Treatment of Gliomas

描述(由申请人提供)：尽管外科和医学上取得了进步，恶性胶质瘤患者的预后仍然严峻。为了应对这一挑战，我们提出了一个计划，该计划将首次结合治疗弥漫性恶性胶质瘤的两大技术进步：靶向胶质瘤干细胞(GSCs)的新型药物和用于对流增强递送(CED)的基于纳米技术的新型递送系统。我们相信，一种基于生物学的设计方法，即我们选择对脑瘤持续存在最重要的细胞具有高活性的药物，将使我们能够设计用于CED的可控释放纳米粒，这些药物针对胶质瘤的治疗进行了优化。在这个项目中，我们将检验这样一种假设，即载药的聚合物纳米颗粒可以通过CED输送到脑肿瘤，并且将这些纳米颗粒装载到因其针对GSCs的生物活性而特别挑选的药物可以加强对颅内肿瘤的治疗。我们将通过完成一系列相互关联的具体目标来检验这一假设：通过CED优化纳米颗粒的性质以实现最有效的传递；表征具有增强抗GSCs活性的新型药物；以及在免疫受损的大鼠体内控制传递用于治疗脑内人脑胶质瘤的新型药物。 公共卫生相关性：恶性胶质瘤是成人最常见的原发恶性脑肿瘤。美国每年新增确诊病例超过15,000例。这一研究项目将导致恶性胶质瘤治疗的新方法的开发。

DESCRIPTION (provided by applicant): Despite surgical and medical advances, the prognosis for patients with malignant gliomas remains grim. To address this challenge, we propose a program that will combine-for the first time-two major advances in technology for treating diffuse malignant glioma: novel drugs that target glioma stem cells (GSCs) and new nanotechnology-based delivery systems designed for use with convection-enhanced delivery (CED). We believe a biology-based design approach, in which we select drugs that have high activity against the cells that are most important in the persistence of brain tumors, will allow us to design controlled release nanoparticles for CED of drugs that are optimized for the treatment of gliomas. In this project, we will test the hypothesis that drug-loaded, polymer nanoparticles can be delivered to brain tumors by CED, and that loading these nanoparticles with drugs specifically selected for their biological activity against GSCs can enhance treatment of intracranial tumors. We will test this hypothesis by completion of an inter-related set of specific aims: optimization of the properties of nanoparticles for most effective delivery via CED; characterization of novel agents with enhanced activity against GSCs; and controlled delivery of novel agents for treatment of intracranial human gliomas in immunocompromised rats. PUBLIC HEALTH RELEVANCE: Malignant gliomas are the most common primary malignant brain tumors in adults. More than 15,000 new cases are diagnosed in the United States each year. This research project will result in the development of new methods for the treatment of malignant gliomas.