Dartmouth Center of Cancer Nanotechnology Excellence
Ian Baker, D.Phil.
Keith Paulsen, Ph.D.
Project 1: Optimization of Nanoparticle Targeting in Ovarian and Breast Cancer
Project Investigators: Tillman Gerngross, Ph.D., and Karl Griswold, Ph.D.
The central hypothesis driving this Project is that the clinical efficacy of magnetic nanoparticle (mNP) based cancer therapies can be substantially enhanced by precise targeting of the particles to cancer cells. Previous efforts using antibody and antibody fragments to target nanoparticles have yielded mixed results, and the fragmented nature of the related literature is not permissive to drawing informative conclusions that might guide future studies. To remedy this stark deficit of knowledge regarding targeting of mNP cancer therapies, this project will, in a controlled fashion, conjugate genetically engineered scFvs to the surface of custom designed mNPs. These mNP immunoconjugates will be subjected to rigorous physical, biochemical, and functional characterization using in-house assays and through collaboration with other DCCNE entities.
Project 2: Spectroscopic Quantification of Ligand Binding In Vivo
Project Investigators: John Weaver Ph.D., and Brian Pogue, Ph.D.
Understanding whether targeted magnetic nanoparticles (mNPs) are actually binding to the targeted site in vivo is critical to developing effective delivery methods to maximize their therapeutic and diagnostic potential. Thus, this Project will develop and validate a fundamentally unique way to quantify targeted mNP ligand binding and distribution in vivo. This quantification will provide data that can lead to mechanistic insight required to interpret why coated nanoparticles collect where they do in the body and how targeted delivery can be optimized and improved substantially. Specifically, the technology will combine optical ratiometric fluorescence spectroscopy with magnetic spectroscopy of particle Brownian motion to quantify bulk concentration uptake and the level of specific binding to the target ligands in vivo, initially on HER2- targeted mNPs.
Project 3: Optimization of Magnetic Nanoparticle Breast Cancer Treatment
Project Investigator: P. Jack Hoopes, D.V.M., Ph.D.
This Project will determine the biodistribution and toxicity/safety of antibody-directed and non-labeled iron oxide nanoparticles, in tumor-bearing and non-tumor-bearing mice. A variety of whole antibodies, antibody fragments, and mNPs will be studied. The most successful of these constructs will be used in murine xenograph mNP tumor treatment efficacy studies. Magnetic nanoparticles (mNP) hyperthermia will be assessed as a stand-alone therapy and in combination with radiation and/or chemotherapy. Specific strategies for increasing mNP deposition in tumors will be studied. Modeling and phantom experiments designed to understand and optimize AMF parameters in the clinical setting will be performed both in vitro and in vivo.
Project 4: Magnetic Nanoparticle Immunotherapy against Ovarian Cancer
Project Investigators: Steve Fiering, Ph.D., Mary Jo Turk, Ph.D., and Josť Conejo-Garcia, M.D., Ph.D.
This Project will define the potential of treating ovarian cancer with magnetic nanoparticle (mNP) hyperthermia. The hypothesis is that superior therapeutic benefits can be achieved by combining mNP-mediated thermoablation of tumor cells with thermoablation of crucial immunosuppressive/pro-angiogenic tumor leukocytes and these treatments will synergize with standard chemotherapies. The studies will be performed both in vivo in a mouse model of syngeneic orthotopic highly aggressive ovarian cancer and in vitro using freshly dissociated human ovarian tumors.