6th Annual Cancer Nanobiology Think Tank
The Center for Cancer Research Nanobiology Program (CCRNP) pursues an integrated, multidisciplinary program to understand the structure and function of biomolecules and their assemblies at the nanoscale, investigate engineering principles of nanomachineries used in living cells, and develop experimental and computational tools enabling nanotechnology-based diagnostics, vaccines and therapeutics to combat cancer and AIDS.
Nanobiology offers many new exciting approaches to the problems of diagnosing, preventing and curing cancer and other diseases. Nanobiology brings together diverse multidisciplinary research groups to solve problems that are associated with nanodesign. In order to establish and strengthen lines of communication between multidisciplinary researchers from CCR and the intramural and extramural communities we have organized annual Nanobiology Think Tank workshops at the NCI-Frederick for the past five years. The aim is to discuss nanotechnology-, nanobiology-, and nanomedicine-related issues and become more informed about current research and future developments in these fields.
These one-day workshops are organized along a particular theme in Nanobiology.
For 2011 we have centered the workshop on the theme of Triggered Nanoparticles. The basic concept is that tumor-specific delivery of anticancer agents may be improved by providing the nanoparticles a disruption mechanism that occurs specifically at the site of tumor. The disruption mechanism may be provided by external forces such as heat, light, alternating magnetic fields or by exploitation of the tumor-specific biology (e.g. enzymes, pH, redox) of the cancer cells. We have invited experts from the multidisciplinary research areas of triggered chemotherapy to participate and lead towards the ensuing brainstorming sessions and discussions in this very important area.
The 6th Annual Cancer Nanobiology Think Tank will be devoted to Triggered Nanoparticles from principles of triggering, design considerations to possible clinical applications and future directions. In particular, we plan to focus the discussion on currently available strategies, approaches, and mechanisms of triggered drug release from various nanoparticles. For the 6th Annual Cancer Nanobiology Think Tank, we have invited speakers who will bring their expertise to bear on the various facets of this theme. Brainstorming sessions focused around the talks, discussions, and questions that arise will follow their presentations. Participants are encouraged to submit abstracts related to the theme of the Think Tank and they will have the opportunity to present their studies in poster sessions during the day. The invited speakers are:
Mark W. Dewhirst, DVM, Ph.D., Gustavo S. Montana Professor of Radiation Oncology, Professor of Pathology and Biomedical Engineering, Duke University Medical Center, Durham, North Carolina
The underlying themes of Dr. Dewhirst's work is in tumor hypoxia, angiogenesis and drug transport, with an emphasis on translational research, and the potential role of hyperthermia to augment selective drug delivery to tumors. He has pioneered new methods for improving tumor oxygenation and has worked with clinical faculty to test these concepts in patients, as means to improve radiation and chemotherapy response. He has recently shown that radiation therapy initiates stabilization of HIF-1, a hypoxia inducible promoter, even in aerobic conditions. HIF-1 stabilization leads to upregulation of angiogenesis, thereby protecting the tumor against radiation damage. This discovery has led to clinical trials targeting HIF-1 stabilization post radiotherapy and chemotherapy as a means to achieve chemo and radiosensitization. His research is also focused to address the question of tumor hypoxia during early tumor angiogenesis to reveal complex patterns of oxygen delivery to tumors, which undoubtedly gives rise to hypoxia reoxygenation injury. He has spearheaded the development of in vivo applications of temperature sensitive liposomes, which increase drug delivery to heated sites by a factor of 30 compared with free drug. Clinical applications of liposomes became apparent with the development of "stealth" liposomes (pegylation), which made them less susceptible to opsonization and RES uptake. Such a liposome loaded with high amounts of doxorubicin (Doxil) has been approved by the FDA. Dr. Dewhirst's group has developed a thermosensitive version of this platform (thermodox), which is now at the point of undergoing phase 3 trials.
Amit Joshi, Ph.D. Assistant Professor of Radiology, Leader of the Computational Tomography Core, Division of Molecular Imaging, Baylor College of Medicine, Houston, Texas
Dr. Amit Joshi also holds an adjunct appointment in Electrical and Computer Engineering at Rice University. His research interests include Integrating methods of large-scale particle transport modeling, nonlinear optimization, and nanophotonics based multimodal molecular imaging; Dr Joshi's main research activities are focused towards the simultaneous imaging and external field modulated therapy of cancer. Currently, he is conducting research on the cross-platform implementation of particle transport simulation tools derived from nuclear research towards fluorescence imaging in mice models of human disease. He is also working on breast and pancreatic cancer theranostics with multimodal gold nanostructures, which dramatically enhance the NIR fluorescence, while providing a strong MR contrast. By shifting the externally applied optical or magnetic fields, the same agents convert to thermally ablative cancer therapeutic probes. Dr. Joshi is engaged in extensive cross field collaborations: with applied mathematicians, resulting in the development of pioneering adaptive finite element methods for optical tomography, with chemists, resulting in the development of multifunctional gold nanostructures, and with cancer biologists resulting in the development of novel molecularly targeting breast and pancreatic cancer theranostics. In collaboration with researchers at Rice University, Dr. Joshi has created a nanoparticle platform trackable with MRIs that locates cancer cells, tags them with a fluorescent dye, and kills them with heat -- a first example of "theranostic," or essentially patient-customized, medical treatment.
Alexander (Sasha) V. Kabanov, Ph.D., Dr.Sc., Parke-Davis Professor of Pharmaceutical Sciences, College of Pharmacy, Director, Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska
Dr. Kabanov's research interests encompass the interface of physical chemistry, life sciences and medicine. Particular emphasis is being placed on the use of polymers in therapeutics as well as fundamental studies on structure and environmentally induced transitions of self-assembled polymer materials. His current research includes the use of polymers for gene therapy, evaluation of block copolymer-based therapeutics to overcome drug resistance in treating cancer as well as improving drug delivery to the brain by inhibiting drug efflux systems. The laboratory is also very active in developing novel classes of environmentally and chemical-stimuli responsive polymer materials on the basis of block ionomer complexes.
Donald M. Engelman, Ph.D. Eugene Higgins Professor, Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut
Dr. Engelman is a world-renowned expert in the area of biomembranes, protein folding and lipid-protein interactions. His research is focused on how the primary sequences of membrane proteins determine their three dimensional structures, and hence their functions. The folding of integral membrane proteins clearly differs from that of soluble proteins since the membrane environment imposes constraints on polypeptide secondary and tertiary structural features quite different from those imposed by an aqueous environment. His recent activities address the use and mechanism of spontaneous, pH-dependent insertion of a water-soluble peptide to form a helix across lipid bilayers. He has used a related peptide, pH (low) insertion peptide (pHLIP), to translocate cargo molecules attached to its C- terminus across the plasma membranes of living cells. This system is also used for various types of molecules attached by disulfides that can be released by reduction in the cytoplasm, including peptide nucleic acids, a cyclic peptide (phalloidin), and organic compounds. Because a high extracellular acidity is characteristic of a variety of pathological conditions (such as tumors, infarcts, stroke-afflicted tissue, atherosclerotic lesions, sites of inflammation or infection, or damaged tissue resulting from trauma), the pH (low) insertion peptide may prove a useful tool for selective delivery of agents for drug therapy, diagnostic imaging, genetic control, or cell regulation. The pHLIP technology introduces a new concept to detect, target, and possibly treat acidic diseased tissue by employing the selective insertion and folding of membrane peptides.