New Multifunctional Quantum Dot Platforms for Tracking Coupled Proteolytic Activity or Combined Diagnosis and Therapy

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Nanoparticles represent a new frontier for chemistry and spectroscopy aimed at the detection of biomarkers associated with diseases and pathogens. Their size is sufficiently small to access biological environments, such as cells, yet their surface area is sufficiently large to permit diverse chemical and biological functionalization. These properties are further complemented by unique size-dependent optical and electronic properties. We propose to use a type of brightly luminescent semiconductor nanoparticle, called a "quantum dot (QD)," as a platform to detect protease activity using fluorescence spectroscopy. Proteases are enzymes that are involved in a large number of biological signaling processes; aberrations in proteolytic activity are implicated in some cardiovascular and inflammatory diseases, many types of cancer, osteoporosis, certain neurological disorders, and the virulence of many pathogens (e.g. HIV, malaria). Two important scientific challenges are (1) better understanding how proteases function, including their complex relationships with one another in signaling networks and cascades, and (2) improving our ability to simultaneously detect the activity of multiple proteases in biological samples and environments. We propose to address these challenges with research in three areas. First, we will design prototype QD-based diagnostic platforms that can measure the activity of multiple proteases in biological samples with only a connection to a laptop computer, thus potentiating bedside diagnostics. Second, we will construct QD probes that can be used to visualize the activation of one protease by another within cells to help elucidate biological function, which is critical for developing new diagnostics or therapies that target proteases. Finally, we will explore the design of new QD probes that can provide concurrent diagnostic and therapeutic utility by integrating detection with inhibitory effects. In each case, the combined luminescent properties, size, and surface area of QDs will uniquely permit these prospective innovations. This research further develops our knowledge of how to use nanotechnology to address biomedical challenges, which, in the long-term, is expected to lead to better healthcare for Canadians.