Tumor Targeting and Diagnostic Applications of Glycosylated Nanotubes

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Positron emission tomography (PET) is the most accurate way to stage and monitor many types of cancer. Although accuracy in detecting tumors larger than 2 cm is high, PET may miss approximately one third of invasive cancers smaller that 1 centimeter. As early and accurate diagnosis is still the most effective approach to treating cancer, improvements in the use of imaging technology to detect and monitor cancer will have a dramatic effect on human health. The goal of this research is to develop a new agent based on multiwalled carbon nanotubes (MWCNT) for the diagnosis and monitoring of advanced breast cancer. MWCNT consist of sheets of graphene carbon rolled into multiwalled tubes and possess many properties that make them extremely useful in biomedical applications, including targeted molecular imaging. Cancer cells have alterations in the normal metabolism of the sugar, glucose, and exhibit increased glucose uptake and decreased glucose clearance. The hypothesis to be tested in this research proposal is that MWCNT targeted to glucose receptors will be taken up by cancer cells with high efficiency, and that such MWCNT can be engineered to be effective PET imaging/ cancer diagnostic agents. The nanotubes will be chemically engineered to display deoxyglucose on their surface, which will render them water soluble, and target them to tumors. Deoxyglucose bound to MWCNT will be labelled with the positron emitter, 18F, enabling the nanotubes to serve as a sensitive imaging tool for positron emission tomograpghy (PET). MWCNT also will be labeled with the beta radiation emitter, 3H-deoxyglucose, for long-term biodistribution and clearance studies. Carbon nanotubes offer many advantages for targeted molecular imaging techniques such as PET: foremost is their ability to deliver large numbers of imaging agents per each targeted molecular recognition, which can improve the sensitivity of imaging; secondly, they can deliver several different types of imaging agents (such as magnetic resonance imaging or photoacoustic agents) to perform multimodality imaging; thirdly, they can be used for therapeutic applications including chemotherapeutic drug or gene delivery, and as mediators for photothermal cancer therapy. Collective, the proposed research will provide: 1) a new, glycosylated MWCNT which can be traced by radiolabelling; 2) data on clinically-relevant issues relating to blood compatibility, and preclinical data on toxicity (clot formation), biodistribution, blood, urinary, and fecal clearance of glycosylated MWCNT injected intravenously into mice, all of which will be essential for any future translational applications; 3) a new, preclinically-optimized nanomedical platform technology, developed specifically to target and diagnose invasive breast cancer, but with broad applicability to many types of cancer. It is anticipated that this agent will serve as the basis for a multimodal platform for future combined cancer therapy and diagnostic applications.