Nanoparticles and Nanocapsules for Glioma Targeting

描述(申请人提供)：恶性胶质瘤是一种对当前治疗反应不佳的异质肿瘤家族。有效处理这些损伤的一个主要障碍是难以向肿瘤细胞输送足够浓度的治疗药物。此外，无法对治疗剂的分布进行成像，阻碍了后续治疗的计划。LNK ChemSolutions，LLC(LNK)，一家小型商业实体，和芝加哥大学医院(UCH)一直致力于开发一种用于靶向递送治疗剂的新型聚合物纳米颗粒(NP)。在初步研究中，我们已经证明了壳层中含有磁铁矿的NPs是否可以通过对流增强传递(CED)在啮齿类动物的大脑中分散，II。运输有效的化疗药物和III。通过标准磁共振成像(MRI)进行可视化。我们第二阶段计划的总体目标是结合以上概述的特定特性来开发一种可用于脑肿瘤成像引导治疗的NP。在整个研究期间，核电厂将在LNK制造，随后在联合医院进行测试。在目标1中，我们将使用体外和动物模型来严格检查NPs对靶向和传递化疗和siRNA的作用。在确定了具有体内靶向和治疗所需特征的典型NP之后，我们接下来将研究将这些NP注入正常动物大脑的潜在毒性效应。在目标2中，我们将利用这些聚合物、含磁性纳米颗粒(PMNPs)进行MRI成像的能力，并测试与非引导治疗相比，多重成像引导治疗是否可以改善治疗反应。在对移植了胶质瘤的啮齿动物的研究之后，在目标3中，我们将继续研究自发性犬脑胶质瘤中的PMNPs。狗的大脑比大鼠大得多，更重要的是，狗的胶质瘤具有许多人类肿瘤的特征。在检测了PMNP对正常犬的毒性后，我们将把患有自发性肿瘤的犬纳入一项特定的方案，包括化疗包裹的NPs的CED。动物将接受治疗，并进行实时磁共振成像和NP分布模式和动物存活记录。虽然UCH正在完成前三个目标，但LNK将同时进行研究，以改进EDH制造技术，特别是优化具有CED所需特性(即直径和100 nm)的NPs的生产(目标4)。随着上述目标的完成，预计我们将开发出一种有效地制造靶向纳米颗粒载体的方法，该载体可用于输送一系列治疗恶性脑肿瘤的药物。重要的是，这种产品还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.