Nanoparticles and Nanocapsules for Glioma Targeting

描述（由申请人提供）：恶性胶质瘤代表了一个异质性肿瘤家族，对当前治疗反应不良。有效管理这些病变的主要障碍涉及难以向肿瘤细胞递送足够浓度的治疗剂。此外，无法对治疗剂的分布进行成像妨碍了后续治疗的计划。LNK Chemsolutions，LLC（LNK）是一家小型企业实体，与芝加哥大学医院（UCH）合作开发了一种新型聚合物纳米颗粒（NP），用于靶向递送治疗剂。在初步的研究中，我们已经证明，纳米粒子轴承磁铁矿在他们的外壳，可以。通过对流增强递送（CED）分散在啮齿动物脑中，ii.转运有活力的化疗剂，和iii.通过标准磁共振成像（MRI）可视化。我们的第二阶段提案的总体目标是将上述特定性质结合起来，以开发可用于脑肿瘤的图像引导治疗的NP。在整个研究期间，NP将在LNK生产，随后在UCH进行检测。在目标1中，我们将使用体外和动物模型来严格检查用于靶向和递送化疗和siRNA的NP。在确定了具有体内靶向和治疗所需特征的原型NP后，我们接下来将研究与将这些NP输注到正常动物脑中相关的潜在毒性作用。在目标2中，我们将利用这些聚合的、带有磁铁矿的NP（PMNP）通过MRI成像的能力，并测试与非引导治疗相比，多次成像引导治疗是否可以改善治疗反应。在啮齿类动物中进行神经胶质瘤异种移植研究后，在目标3中，我们将继续研究自发性犬神经胶质瘤中的PMNP。狗的大脑比大鼠大得多，更重要的是，狗的神经胶质瘤具有人类肿瘤的许多特征。在检查正常狗中的PMNP毒性后，我们将招募患有自发性肿瘤的伴侣狗进入涉及化疗包封的NP的CED的特定方案。将对动物进行处理，并通过实时MR成像和NP分布模式进行随访，并记录动物存活率。在UCH完成前3个目标的同时，将在LNK同时进行研究，以改进EDH生产技术，特别是优化具有CED所需特性（即直径< 100 nm）的NP的生产（目标4）。在完成上述目标后，预期我们将开发出一种有效制造靶向纳米颗粒载体的方法，该载体可用于递送一系列用于治疗恶性脑肿瘤的治疗剂。重要的是，这种产品也有可能对神经系统内外的其他疾病的管理产生重大影响。

DESCRIPTION (provided by applicant): Malignant gliomas represent a heterogeneous family of tumors that are poorly responsive to current treatments. A major obstacle to the effective management of these lesions involves the difficulty in delivering adequate concentrations of therapeutics to the tumor cells. In addition, the inability to image the distribution of therapeutic agent hampers the planning of subsequent treatments. LNK Chemsolutions, LLC (LNK), a small business entity, and the University of Chicago Hospitals (UCH), have been engaged in the development of a novel polymeric nanoparticle (NP) for the targeted delivery of therapeutic agents. In preliminary studies, we have demonstrated that NPs bearing magnetite within their shell, can i. be dispersed in the rodent brain by convection enhanced delivery (CED), ii. transport viable chemotherapeutic agent and iii. be visualized by standard magnetic resonance imaging (MRI). The overall goal of our Phase II proposal is to incorporate the specific properties outlined above to develop an NP that can be used for imaged-guided treatment of brain tumors. Throughout the study period, NPs will be manufactured at LNK and subsequently tested at UCH. In Aim 1, we will use both in vitro and animal models to critically examine NPs for targeting and delivery of chemotherapy and siRNA. After identifying a prototypical NP that has the necessary characteristics for in vivo targeting and therapy, we will next investigate potential toxic effects related to infusion of these NPs into normal animal brains. In Aim 2, we will harness the ability of these polymeric, magnetite-bearing NPs (PMNPs) to be imaged by MRI, and test whether multiple imaged- guided treatments can improve the therapeutic response compared to unguided treatments. Following studies in rodents with glioma xenografts, in Aim 3 we will move on to study PMNPs in spontaneous canine gliomas. Dogs have significantly larger brains than rats and, more importantly, canine gliomas have many of the characteristics of human tumors. After examining PMNP toxicity in normal dogs, we will enroll companion dogs with spontaneous tumors into a specific protocol involving CED of chemotherapy encapsulated NPs. Animals will be treated and followed with real-time MR imaging and NP distribution pattern and animal survival documented. While the first 3 Aims are being completed at UCH, at LNK studies will concurrently be conducted to improve the EDH manufacturing technique specifically to optimize production of NPs that have characteristics necessary for CED (i.e. diameter < 100 nm) (Aim 4). Following the completion of the above Aims, it is anticipated that we will have developed a method to efficiently manufacture a targeted nanoparticle vector that can be used to deliver a range of therapeutics for the treatment of malignant brain tumors. Importantly, such a product also has the potential to make a significant impact in the management of other diseases both in and outside of the nervous system.