Matrix Metalloproteinase-Responsive Superparamagnetic Iron Oxide Nanoparticles (SPIONs) to Distinguish Between Aggressive and Indolent Cancer
Type of DegreePhD Dissertation
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Biomedical imaging modalities play a key role in the detection and accurate characterization of cancer lesions. While anatomical imaging modalities provide essential information about the location and size of a tumor lesion, they provide little regarding the genetic and molecular abnormalities that characterize various stages of tumorigenesis. On the other hand, molecular imaging modalities detect molecular level changes associated with early stages of tumor progression. Proteases are a class of biomolecules that are heavily involved in tumorigenesis, both at the primary and metastatic sites. The expression of one specific protease, matrix metalloproteinase-2 (MMP-2), correlates with tumor grade, and its catalytic nature and presence in the tumor microenvironment make it an excellent imaging target. While several imaging agents have already been developed to detect MMP-2 activity in the tumor microenvironment, the majority suffer from glaring limitations that hamper clinical success. The goal of this project was to develop a pharmacokinetically stable and tumor targeting imaging agent, based on superparamagnetic iron oxide nanoparticles (SPIONs), for quantifying MMP-2 activity. SPIONs were chosen as the base material due to their favorable toxicity profiles, biocompatibility, and unique physiochemical properties. The surface of SPIONs was decorated with an MMP-2 specific peptide for protease targeting, polyethylene glycol (PEG) for colloidal stability, Cy7 fluorophore for in vivo tracking with multispectral optoacoustic tomography (MSOT), and an RGD peptide for active tumor targeting. Extensive in vitro and in vivo characterization of the imaging agent was conducted, with the agent showing tremendous potential as a diagnostic tool for early detection and accurate characterization of tumor lesions.