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Background to Neuromuscular Activity 3 Calcium and Magnesium Effects 5 Muscle Characteristics 9 Labile Nature of Neuromuscular Transmission MATERIALS AND METHODS RESULTS AND DISCUSSIONS Perfusion Techniques Control Data #1: Intact Animal Control Data #2: Normal Krebs Perfusion Modified Krebs #1: Decreased [Ca**] and Normal [Mg^] Modified Krebs #2: Decreased [Ca**] and Increased [Mg**] Modified Krebs #3: Decreased [Mg^] and Normal [Ca^^] Modified Krebs #4: Decreased [Mg^] and Decreased [Ca**] 52 Stimulus Threshold Voltages 59 Tetanic Contractions

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Survival statistics for glioblastoma multiforme (GBM) have remained static despite years of research. Two challenges must be overcome to extend survival: drug delivery and resistance to current therapies. Recently, we have developed a highly-penetrative polymeric nanoparticle system capable of being safely delivered to brain parenchyma using convection-enhanced delivery (CED). We have previously shown that this system is capable of protecting and releasing in a controlled manner agents with activity against glioma stem cells (GSCs), significantly improving survival in a rat xenograft model of GSC-derived GBM. We describe here our efforts to further refine this potential therapeutic. First, utilizing high-throughput small molecule screening of a library of generic and FDA- and internationally-approved compounds against GSCs of varying morphologies and genetic composition, we describe the discovery of a novel class of compounds with profound anti-proliferative activity against GSCs but with only very limited activity against normal glial cells. Identified compounds are notably small and lipophilic, making them ideal candidates for translation in our highly-penetrative polymeric nanoparticle system. Second, building upon recent advances in magnetic resonance imaging technology, we describe the incorporation of supraparamagnetic iron oxide (SPIO) in our highly-penetrative polymeric nanoparticle system. We show that incorporation of SPIO does not alter size or in vitro properties of these nanoparticles. Further, we show that SPIO-loaded nanoparticles can be safely delivered to brain parenchyma using CED and can stably release their contents in a controlled fashion over a matter of weeks. These results represent important steps toward clinical application of a promising drug delivery technology. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A86. Citation Format: Garth W. Strohbehn, Komli-Kofi Atsina, Toral R. Patel, Joseph M. Piepmeier, Jiangbing Zhou, W. Mark Saltzman. Preclinical refinement of a highly-penetrative polymeric nanoparticle drug delivery system for the treatment of glioblastoma multiforme. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A86.