Abstract IA15: Convection-enhanced delivery of nanomaterials for glioma

Current therapy for malignant brain tumors, such as glioblastoma multiforme (GBM), is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two advances in technology: 1) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery (CED); and 2) re-purposed, FDA-approved compounds, which were identified through library screening to target BCSCs. Using fluorescence imaging, positron emission tomography (PET), and magnetic resonance imaging (MRI), we demonstrate that brain-penetrating nanoparticles can be delivered intracranially to large volumes in both rat and pig. We identified several FDA-approved agents that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by CED, one of these agents dramatically increased survival in rats bearing BCSC-derived xenografts. This new approach to controlled delivery in the brain should have a significant impact on treatment of GBM and suggests new routes for drug and gene delivery to treat other diseases of the CNS. Bibliography 1. Sawyer AJ, Saucier-Sawyer J, Booth C, Liu J, Patel T, Piepmeier JM, and Saltzman WM. Convection-enhanced delivery of camptothecin-loaded polymer nanoparticles for treatment of intracranial tumors, Drug Delivery and Translational Research 1:34-42 (2011). PMCID: PMC3117592 2. Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, Duong N, Schafbauer T, Huttner AJ, Huang Y, Carson RE, Zhang Y, Sullivan DJ, Piepmeier JM, and Saltzman WM. Highly penetrative nanocarriers loaded with drugs targeted to resistant cells improve treatment of glioblastoma, Proceedings of the National Academy of Sciences, 110 (29): 11751-11756 (2013). PMCID: PMC3718184 3. Deng Y, Saucier-Sawyer JK, Hoimes CJ, Zhang J, Seo YE, Andrejecsk JW, and Saltzman WM. The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. Biomaterials 35:6595-6602 (2014). PMCID: PMC4062180. 4. Strohbehn G, Coman D, Han L, Ragheb RT, Fahmy TM, Huttner AJ, Hyder F, Piepmeier JM, Saltzman WM, and Zhou J. Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance, Journal of Neuro-Oncology 121:441-449 (2014). PMCID: PMC4323763. 5. Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, Saltzman WM, and Slack FJ. MicroRNA silencing for cancer therapy targeted to the tumor microenvironment, Nature 518:107-110 (2015). PMCID: PMC4367962. 6. Cheng CJ, Tietjen GT, Saucier-Sawyer JK, and Saltzman WM. A holistic approach to targeting disease with polymer nanoparticles, Nature Reviews Drug Discovery 14:239-247 (2015). PMCID: PMC4451203. 7. Saucier-Sawyer JK, Seo Y, Gaudin A, Sawyer AJ, Deng Y, Quijano E, Huttner A, and Saltzman WM. Distribution of nanoparticles after convection-enhanced delivery (CED) in the brain, Journal of Controlled Release 232:103-112 (2016). [PCMID: in process] Citation Format: Mark Saltzman. Convection-enhanced delivery of nanomaterials for glioma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr IA15.