Panos Fatouros - US grants

DESCRIPTION (provided by applicant): There is a need for improved imaging techniques which specifically identify molecular features of glioma cells and which might be used to target antitumor therapies. Convection enhanced delivery is a powerful new technique for delivering targeted molecular therapeutics into the brain. However, this strategy is hindered by potential irregularity of distribution due to tumor cytoarchitecture and an inability to accurately monitor the distribution of the therapeutic agents during and after infusion. Water-soluble trigadolinium nitride endohedral metallofullerenes are an innovative nanotechnology with great potential due to their MRI T1 relaxivity characteristics, approximately two orders of magnitude greater than conventional contrast agents. The metallofullerenes can be affinity labeled for molecular targeting and can have lutetium (Lu) or terbium (Tb) substituted for Gd. Lutetium can be neutron-activated to form 177Lu, an isotope with excellent characteristics for delivering targeted interstitial radiotherapy, while Tb can be visualized due to its fluorescence. We propose a strategy for developing affinity-labeled metallofullerenes as a powerful and innovative nanotechnology platform for targeting glioma cells in vivo, with Gd for MR imaging, with Tb for fluorescence localization, and with Lu for interstitial molecular brachytherapy. The proposed work brings together a number of innovative strategies to develop a nanotechnology platform for planning "real-time" optimal delivery of intra-tumoral therapy. Summary: This project will develop, modify, and characterize metallofullerenes ("buckyballs") as a nanotechnology platform capable of greatly improving brain tumor imaging and of delivering fluorescent labeling and radiation therapy to the tumor cells at the molecular level. Improvements in the detection and treatment of this devastating disease are desperately needed. The ability to simultaneously detect and target therapies at the brain tumor cells holds great promise. Lead Investigators: PP FATOUROS, PhD, Principal Investigator, expert in experimental and clinical imaging, Chair Radiation Physics & Biology; HC DORN, PhD (Virginia Tech), organic chemist and co-inventor of metallofullerenes; WC BROADDUS, MD, PhD, neurosurgeon scientist and Director VCD Neurooncology; J.D. WILSON, PhD, radiobiologist and Director Animal Imaging, VCU Molecular Imaging Center; H. L. FILLMORE, PhD, molecular neurobiologist, expert in tumor targeting strategies.

This proposal was received in response to Nanoscale Science and Engineering initiative, NSF 04-043, category NIRT. This Solid State Chemistry program (DMR) award to Virginia Polytechnic Institute and State University is to develop understanding the mechanism and fundamental dipole-dipole dynamic interactions (i.e., unpaired electron spin density inside/outside the carbon cage with water) responsible for the enhanced relaxivity in functionalized endohedral metallofullerenes (EMFs) when used as medical diagnostic agents and other imaging applications (e.g., polymers, composites). Endohedral metallofullerenes, because of their shape, and capacity for multiple endo encapsulants and exo functionalizability, are ideal nano-constructs on which to develop imaging agents. In addition, the high stability of the carbon cage is known to exhibit unusual resistance to any chemical cage-opening process. The ability to detect and measure low amplitude signals in noisy, complex environments is a fundamental challenge in imaging applications. Although there have been major improvements in biological imaging technology (MRI), the sensitivity and specificity of current techniques using contrast agents such as the one using small molecular chelates of gadolinium remain far from optimal. Although signal amplification is important to achieving this goal, it will not be sufficient; rather it will require a synergistic approach that incorporates multiple visibilities simultaneously into the same nano-construct (multi-modal), not only to increase sensitivity, but also the signal/noise ratio and provide the ability to generate quantitative data. Major goals of this award will be to: 1) provide a new model for understanding the spin-lattice relaxation time (T1) (or increasing relaxivity r1= 1/ T1) of water or tissue, 2) employ this model to optimize these nanoscale interactions, and 3) develop a new multi-modality nanosphere-based endohedral metallofullerene imaging agents. In addition to the Solid-State Chemistry program (MPS), the following programs are co-funding this award: Chemistry (MPS); Engineering Education and Centers (ENG); and Bioengineering and Environmental Systems (ENG).

With this award, new educational programs will be developed at the K-12, undergraduate, and graduate levels, especially in the sciences through Institute for Connecting Science Research to the Classroom (ICSRC), an interdisciplinary center established in the College of Human Resources and Education at the University. In addition, the existing short courses and hands-on laboratory experiments in nanomaterials will be expanded to include other students and faculty at Virginia Tech, Virginia Commonwealth University as well as other academic institutions across the region. These interactions would provide undergraduates and graduate students in other disciplines the opportunity to interact with each other in many areas of nanotechnology. Industrial collaborations with Luna Innovations are expected to produce nanomaterials with potential biomedical imaging applications.