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.

R44CA135906

2008-09-12

2015-08-31