PROJECT SUIVIMARY (See instructions): Malignant glioma (MG) represent the most prevalent and lethal primary cancer of the central nervous system. Patients diagnosed with the highest grade MG, grade IV glioblastoma multiforme (GBM), survive for only 9-12 months after diagnosis despite surgical resection and aggressive treatment regimens. Multimodal approaches using radiation with conjunctive chemotherapy (temozolamlde) resulted in only margina increase in patients'survival up to 14.6 months;recurrence is nearly universal and salvage therapies for such progression remain ineffective. An incomplete understanding of how catalogued genetic aberrations dictate phenotypic hallmarks of the disease, particularly intense therapy (apoptosis) resistance, yet florid intratumoral necrogenesis, combined with a highly therapy-resistant cancer stem cell population (brain tumor stem cells, BTSC) as the putative cell-of-origin conspired to make GBM a highly enigmatic and incurable disease. This grant proposal addresses the critical challenges facing the glioma field on multiple levels: (i) To overcome toxicity, insufficient specificity and delivery of targeted therapies (e.g. (R)TK inhibitors), our efforts focus on gene silencing using novel small interfering RNA (siRNA)-conjugated gold nanoparticles (RNA-Au NPs). This alternative and highly promising new agent exhibits enhanced cellular/tissue uptake, reduced offtarget effects and improved biostability and compatibility compared to conventional molecular RNAi and other polymer and nanoconstructs. (ii) This single-entity RNAi nano-reagent will target concomitantly activated RTKs and Bcl2L12 as GBM signature lesions and functionally validated modulators of therapeutic resistance and neurologically debilitating necrogenesis. (iii) We will pre-clinically validate RTK- and Bcl2L12- targeting NPs (RTK-, L12-RNA-Au NPs) in physiologically highly relevant BTSC and derived orthotopic explant model systems, (iv) We will extend our pre-clinical validation efforts from orthotopic xenograft models to studies of tumor regression in a refined, acute onset, highly penetrant GBM mouse model to assess efficacy of RNA-Au NPs in the setting of an intact immune system and a physiologically more relevant tumor microenvironment.

Public Health Relevance

The continued lack of success in treating GBM with conventional and novel targeted therapies, proven to be effective in other malignancies, has prompted a reevaluation of all aspects of glioma drug development. Using sophisticated cancer stem cell and in vivo mouse models, we wili drive preclinical validation of gold nanoparticles functionalized with small interfering RNA (siRNA) oligonucleotides (RNA-Au NPs) towards pharmaceutical opportunities to make a significant Impact on the life of GBM patients,

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-GRB-S)
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Northwestern University at Chicago
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Calabrese, Colin M; Merkel, Timothy J; Briley, William E et al. (2015) Biocompatible infinite-coordination-polymer nanoparticle-nucleic-acid conjugates for antisense gene regulation. Angew Chem Int Ed Engl 54:476-80
Chinen, Alyssa B; Guan, Chenxia M; Mirkin, Chad A (2015) Spherical nucleic acid nanoparticle conjugates enhance G-quadruplex formation and increase serum protein interactions. Angew Chem Int Ed Engl 54:527-31
Rubert Pérez, Charles M; Stephanopoulos, Nicholas; Sur, Shantanu et al. (2015) The powerful functions of peptide-based bioactive matrices for regenerative medicine. Ann Biomed Eng 43:501-14
Xi, Guifa; Robinson, Erik; Mania-Farnell, Barbara et al. (2014) Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine 10:381-91
Heffern, Marie C; Matosziuk, Lauren M; Meade, Thomas J (2014) Lanthanide probes for bioresponsive imaging. Chem Rev 114:4496-539
Moyer, Tyson J; Finbloom, Joel A; Chen, Feng et al. (2014) pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies. J Am Chem Soc 136:14746-52
Kuhn, Misty L; Zemaitaitis, Bozena; Hu, Linda I et al. (2014) Structural, kinetic and proteomic characterization of acetyl phosphate-dependent bacterial protein acetylation. PLoS One 9:e94816
Kurepa, Jasmina; Nakabayashi, Ryo; Paunesku, Tatjana et al. (2014) Direct isolation of flavonoids from plants using ultra-small anatase TiOýýý nanoparticles. Plant J 77:443-53
Cabezas, Maria D; Eichelsdoerfer, Daniel J; Brown, Keith A et al. (2014) Combinatorial screening of mesenchymal stem cell adhesion and differentiation using polymer pen lithography. Methods Cell Biol 119:261-76
Shabbir, Shagufta H; Cleland, Megan M; Goldman, Robert D et al. (2014) Geometric control of vimentin intermediate filaments. Biomaterials 35:1359-66

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