The Dartmouth Center of Cancer Nanotechnology Excellence (DCCNE) focuses on the development and use of novel antibody-targeted magnetic iron/iron oxide core/shell nanocomposite particles (mNPs) for the treatment of tumors. Several relevant cancer antigens will be targeted by conjugating high-affinity antibody fragments or single-chain variable domains (scFvs) to mNPs. The effort focuses on breast cancer and ovarian tumors, but is applicable to most cancers. The work is timely because it has been shown, using mouse models in several laboratories, including the Hoopes laboratory at Dartmouth, that by amassing magnetic superparamagnetic iron oxide nanoparticles (SPIOs) in a tumor and applying an alternating magnetic field (AMF), tumor cells are damaged to such an extent that either malignant growth is significantly retarded or the tumor is completely destroyed. The DCCNE will improve upon these earlier findings by using mNPs, developed in the Baker lab at Dartmouth, that show superior heating behavior in an AMF when compared with SPIOs. The mNPs will be coated with either dextran or phospholipids and functionalized by covalently attaching scFVs to achieve tumor-specific targeting. A range of novel targeting scFVs will be produced, and tumor accumulation will be examined for a range of mNP sizes (15-100 nm) in mouse and pig models. The breast cancer work will involve development of a tumor treatment strategy to determine the efficacy of direct injection of mNPs into a tumor versus introduction of antibody-conjugated mNPs to the tumor through injection into the vasculature and using an AMF to damage the cancer cells. The ovarian cancer work will involve development of strategies to determine the therapeutic effectiveness of introducing antibody-conjugated mNPs into the peritoneal cavity of preclinical ovarian cancer models and dissociated clinical specimens. In addition, an AMF will be used to damage cancer cells while also eliciting anti-tumor immunity using various chemotherapies. The DCCNE will develop new imaging technologies to determine the binding, location, and concentration of the mNPs based on combining optical ratiometric fluorescence spectroscopy with magnetic spectroscopy of particle Brownian motion in order to produce two novel and synergistic approaches to quantify uptake and the level of binding in vivo. The animal work will occur in the Toxicology, Pathology, and Biodistribution Core. The Biostatistics, Data Analysis, and Computation Core will analyze measurements and calculate the magnetic field for the optimum biologically justified conditions for the animal experiments. The DCCNE will participate fully in NCI CCNE Trans-Alliance activities. Public Health Relevance: The Dartmouth CCNE will use novel biocompatible magnetic nanoparticles targeted to tumors to destroy or severely damage the tumors when an alternating magnetic field is applied. The work will also examine the synergy of combining this approach with chemotherapy to produce anti-tumor immunity. The DCCNE will be focus on breast cancer and ovarian cancer treatment, but the approaches developed potentially can be used for any type of cancer.
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