Nanoparticles and Nanocapsules for Glioma Targeting

描述（由申请人提供）：恶性胶质瘤是一种异质性的肿瘤家族，对目前的治疗反应较差。有效治疗这些病变的一个主要障碍是难以向肿瘤细胞提供足够浓度的治疗药物。此外，无法成像治疗剂的分布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，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，在其外壳内含有磁铁矿的NPs可以通过对流增强输送（CED）在啮齿动物的大脑中分散。运输可行的化疗药物和iii。通过标准磁共振成像（MRI）可见。我们II期提案的总体目标是结合上述特定属性来开发可用于图像引导脑肿瘤治疗的NP。在整个研究期间，NPs将在LNK生产，随后在UCH进行测试。在Aim 1中，我们将使用体外和动物模型来严格检查NPs对化疗和siRNA的靶向和递送。在确定具有体内靶向和治疗所需特征的原型NP后，我们将下一步研究将这些NP输注到正常动物大脑中的潜在毒性作用。在目标2中，我们将利用这些含磁性聚合物NPs （PMNPs）的MRI成像能力，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。在啮齿类动物的神经胶质瘤异种移植研究之后，在Aim 3中，我们将继续研究自发性犬胶质瘤中的PMNPs。狗的大脑比老鼠大得多，更重要的是，狗的神经胶质瘤有许多人类肿瘤的特征。在检查了正常犬的PMNP毒性后，我们将招募患有自发性肿瘤的伴侣犬加入一个特定的方案，包括化疗包埋NPs的CED。对动物进行治疗，并进行实时磁共振成像和NP分布模式的跟踪，记录动物的生存情况。在UCH完成前3个目标的同时，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< 100 nm）的np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制造靶向纳米颗粒载体的方法，该载体可用于提供一系列治疗恶性脑肿瘤的疗法。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治疗产生重大影响。

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.