The Toxicology, Pathology, and Biodistribution Core will provide qualitative and quantitative assessment of the movement and deposition of mNPs in all major organ tissues as well as individual cells in specific settings. The TPB core will also provide dedicated and comprehensive pharmacokinetic (Lewis), human and animal pathology/pathophysiology (Memoli and Hoopes) and TEM/SEM (Daghlian) expertise for potential cellular and/or tissue change resulting from the mNPs (iron, coatings, targeting peptides, fluorescent probes etc and/or the alternating magnetic field (AMF) exposure. Since it is the primary goal of the entire DCCNE application to optimize methods for the observation and selectively delivery of mNP/lron to cancer cells for subsequent cytotoxic excitation, the assessment and quantification of iron levels in cells and tissues (Prussian Blue histomorphometry and ICP-MS) and the resultant pathologic effects in the tumor and normal tissues, is of paramount importance. The TPB Core will be a central participant in the determination ofthe relative ability ofthe various NP physical parameters, coatings, internalizing vs noninternalizing ScFv peptides to selectively target mNP /iron to cancer cells in vitro and in vivo (Project 1). In addition, TEM will allow an accurate assessment of the volume and anatomic location of the various NPs with respect to effective excitation and cytotoxicity. TPB assessments will determine which peptides have the most targeting promise for future use in preclinical in vivo ovarian and breast tumor models (Projects 2 and 3). In Project 2, the TPB will play an essential role determining the accuracy and sensitivity ofthe mNP in vivo imaging techniques. Pathologic co-registration and validation of changes observed by noninvasive imaging techniques such as optical spectroscopy and MRI remains the gold standard for determining the sensitivity and reliability of new imaging techniques. In Project 3, the use of ICP-MS and Prussian Blue histomorphometry mNP /iron quantification techniques will allow investigators to determine the absolute role of mNP/lron content in tumor treatment efficacy studies. In Project 4, the TPB Core will be important in determining the level of iron that is taken up by the ovarian cancer dendritic cells, cancer cells and other abdominal tissues that are exposed to the ip delivered mNPs. Since the targeted NP exposure field, in this cancer model, is large, there Is a risk of normal tissue injury. Pathologic assessment of these mice will be extremely important for safety and the understanding of toxicity/efficacy.

Public Health Relevance

The TPB Core is designed to provide toxicology, pathology, and pharmacokinetic biodistribution support to the Dartmouth CCNE research projects. The primary goals of the Core are to aid Project investigators in identifying and understanding the effects and pharmacokinetic distribution ofthe various mNPs in plasma, tumors, and normal tissues (organs) at various times following their administration.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-GRB-S)
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Dartmouth College
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