"Structural Proteomics of Complex Biological Systems"

Modern biological research is increasingly focused on the network of interactions of biological molecules in the cell, as well as the dynamic localization of these multi-protein complexes. The structures of individual proteins are being determined as part of a number of large scale efforts in structural genomics. The manner in which these proteins interact and form functional cellular networks is also being investigated through co-purification and bioinformatic methods. Many of these biomolecular assemblies are dynamically localized during the cell cycle, and this localization is critical to proper function. The development of approaches and tools for investigating the structural biology of complex systems in the context of the cell is needed to provide an understanding of biology from molecular to cellular. The integration of structural approaches into systems biology requires techniques for atomic and cellular resolution studies, as well as conceptual and computational approaches that facilitate the integration of various experimental and theoretical methods.

"The Workings of NCI Nanotechnology Alliance for Cancer - an Opportunity for a New Class of Diagnostic and Therapeutic Solutions Based on Nanotechnology"

National Cancer Institute is engaged in efforts to harness the power of nanotechnology to radically change the way we diagnose and treat cancer. Novel and multi-functional nanodevices will be capable of detecting cancer at its earliest stages, pinpointing its location within the body, delivering anticancer drugs specifically to malignant cells, and determining if these drugs are effective. Functionalized nanoparticles would deliver multiple therapeutic agents to tumor sites in order to simultaneously attack multiple points in the pathways involved in cancer. Such nano-therapeutics are expected to increase the efficacy of drugs while dramatically reducing potential side effects. In vivo biosensors would have the capability of detecting tumors and metastatic lesions that are far smaller than those detectable using current, conventional technologies. Furthermore, they will provide rapid information on whether a given therapy is working as expected.
In order to further these research goals, NCI Alliance for Nanotechnology in Cancer has been formed in 2004. The Alliance is investing $144.3 million over the next 5 years to pursue applied nanotechnologies for cancer detection, therapy, and prevention with an aim to achieve clinical translational stage of these technologies towards culmination of the program. The Alliance funds Centers of Cancer Nanotechnology Excellence, the development of nanotechnology platforms, and intramural Nanotechnology Characterization Laboratory (NCL). NCL provides a spectrum of data on the physical parameters and pharmacological and toxicological characteristics of clinically promising nanomaterials.

The eight CCNEs - Centers of Cancer Nanotechnology Excellence represent prime research institutions in the US: Carolina Center of Cancer Nanotechnology Excellence at the University of North Carolina, Center for Cancer Nanotechnology Excellence Focused on Therapy Response at Stanford University, Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer at the University of California, San Diego, Emory-Georgia Tech Nanotechnology Center for Personalized and Predictive Oncology at Emory University and Georgia Institute of Technology, MIT-Harvard Center of Cancer Nanotechnology Excellence at MIT and Harvard University, Nanomaterials for Cancer Diagnostics and Therapeutics at Northwestern University, Nanosystems Biology Cancer Center at California Institute of Technology, and the Siteman Center of Cancer Nanotechnology Excellence at Washington University.
This presentation will describe the details behind the organization and science and technology of the Alliance.

"Using nanotechnology for vascular proteomic mapping and targeted penetration into specific organs and tumors in vivo"

New targeting strategies may help fulfill the promise of molecular medicine and nanotechnology for clinical imaging and therapy. Overcoming in vivo barriers to systemically deliver nanoparticles inside specific tissues remains a challenge. Vascular endothelial cells form a key barrier restricting access inside most tissues. Yet luminal surfaces of endothelia are directly in contact with circulating blood and thereby provide an inherently accessible interface for targeting in vivo. Caveolae abundant at the surface of endothelia provide a means to cross the normally restrictive endothelial cell barrier. Here, we use nanoparticles to coat and to isolate luminal endothelial plasma membranes and their caveolae directly from tissue. We integrate this fractionation with subtractive proteomic mapping, bioinformatic interrogation, and dynamic live molecular imaging to identify and validate tissue-specific endothelial targets that are accessible to antibodies and nanoparticles injected intravenously. This proteomic mapping reveals distinct molecular signatures for endothelial surfaces and caveolae in solid tumors and organs.
Specific antibodies can target 5-25nm nanoparticles to enter caveolae for rapid transendothelial transport into the tissue interstitium. Caveolae act as active pumps transporting specific molecular cargo, even against a concentration gradient, to concentrate select antibodies in the tissue interstitium. Such pervasive access improves the efficacy of radioimmunotherapy in destroying both stromal and tumor cells. The unprecedented speed in immunotargeting and caveolar transcytosis in vivo underscores the physiological function for caveolae in transvascular exchange and encourages targeting caveolae as a worthwhile novel strategy to enhance nanoparticle delivery in vivo. Our discovery & validation strategy may help uncover targets potentially useful for non-invasively detecting, characterizing, treating, and even monitoring many tumor types in the clinic.