Project 1: Targeted Nanoparticle Therapeutics for Treating Intracranial Disease

项目1：用于治疗颅内疾病的靶向纳米颗粒疗法。 摘要： 患有原发脑癌和其他癌症脑转移的患者很难治疗，因为大多数 系统给药的治疗药物不会到达颅内疾病。血脑屏障(BBB) 限制许多小分子药物和基本上所有大分子治疗剂(肽、蛋白质、 核酸)到达大脑。虽然一些颅内肿瘤最终会突破血脑屏障，但这 该项目的重点是通过完整的血脑屏障接触到疾病。我们建议创建一个有针对性的 穿透完整血脑屏障的纳米颗粒(NP)可为小鼠颅内肿瘤提供治疗药物 人类疾病的模型。在这里，我们将使用胶质母细胞瘤的小鼠模型开始我们的研究 (GBM)。 Davis团队已经将两种不同的NPs转化为各种癌症的临床研究(CRLX101[1]- 含有小分子药物，而CALAA-01[2，3]-含有siRNA)。NP CALAA-01利用转铁蛋白 以表面受体靶向剂和siRNA为治疗实体。最近，戴维斯的团队展示了 如果含有转铁蛋白的纳米粒的性质设计得当，它可以穿过小鼠体内完整的血脑屏障[4]。这里, 我们将利用这些发现来创造可以运输单一或多种治疗药物的靶向NPs (NSBCC的中心主题)从小鼠的全身给药穿过血脑屏障进入基底膜肿瘤。 该项目的成功完成将为解决颅内疾病提供治疗方法。 因为100 nm以下的纳米粒子将成为输送载体，包括多种治疗实体(通过 项目4)在国家方案内产生的结果将允许采用组合战略。 虽然这项工作将从单一小分子药物的交付开始，但成功将使 多种小分子药物，并扩展到单独和组合的大分子治疗 探员们。

PROJECT 1: Targeted Nanoparticle Therapeutics for Treating Intracranial Disease. ABSTRACT: Patients with primary brain cancers and brain metastases from other cancers are difficult to treat, as most systemically administered therapeutic agents do not reach intracranial disease. The blood-brain barrier (BBB) limits many small molecule drugs and essentially all macromolecular therapeutic agents (peptides, proteins, nucleic acids) from reaching the brain. While some intracranial tumors can eventually breach the BBB, this project focuses on reaching disease that is accessible via an intact BBB. We propose to create a targeted nanoparticle (NP) that crosses an intact BBB to deliver therapeutic agents to intracranial tumors in mouse models of the human disease. Here, we will initiate our investigations using mouse models of glioblastoma (GBM). The Davis group has translated two different NPs into clinical studies for a variety of cancers (CRLX101[1] – contains a small molecule drug, and CALAA-01 [2,3]- contains siRNA). The NP CALAA-01 utilizes transferrin for surface receptor targeting agent and siRNA as the therapeutic entity. Recently, Davis' group showed how transferrin-containing NPs can cross an intact BBB in mice if the NP properties are properly designed [4]. Here, we will exploit those findings to create targeted NPs that can transport single or multiple therapeutic agents (the central NSBCC theme) across the BBB and into GBM tumors from systemic administrations in mice. Successful completion of this project will provide therapeutic modalities to address intracranial disease. Because sub-100 nm NPs will be the delivery vehicles, inclusion of multiple therapeutic entities (informed via the results that emerge from Project 4) within the NPs will allow combination strategies to be employed. Although work will begin with delivery of a single small molecule drug, success will enable combinations of multiple small molecule drugs, and extensions to individual and combinations of macromolecular therapeutic agents.