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Tetraphenylphosphonium as a Novel Molecular Probe for Imaging Tumors

Department of Radiology and the Bio-X Program, Stanford University School of Medicine, Stanford, California

Mitochondrial membrane potential (m)–dependent enhanced uptake of phosphonium salts, including ³H-tetraphenylphosphonium (³H-TPP), in tumor cells, suggests the potential use of phosphonium salts as tracers for tumor imaging. In this study, we characterize the tumor accumulation of ³H-TPP and compare it with ¹⁸F-FDG in cell culture and in xenograft, metastatic, and inflammation models in living animals. Methods: ³H-TPP and ³H-FDG accumulation was compared in cell culture with a variety of cell lines in different glucose concentrations. Normal biodistribution and tumor uptake were assessed using nude mice with or without subcutaneous xenograft tumors (C6). To compare the accumulation of ³H-TPP and ¹⁸F-FDG in a metastatic tumor, severe combined immunodeficiency mice were tail-vein injected with human melanoma cell lines (A375-FL). To characterize the accumulation of ³H-TPP and ¹⁸F-FDG in inflammation, an inflammatory reaction was induced by subcutaneous injection of Complete Freund’s Adjuvant in the left hind paw of Sprague–Dawley rat. Results: The m data from a separate study and the current ³H-TPP uptake data showed good correlation (r² = 0.82, P < 0.05). ³H-TPP accumulation was significantly greater than that of ³H-FDG for glucose 100 mg/dL. The biodistribution study of ³H-TPP showed low uptake in most tissues but high accumulation in the heart and kidneys. ³H-TPP accumulation in xenograft or metastatic tumors was comparable with that of ¹⁸F-FDG, whereas ³H-TPP accumulation in inflammatory tissues was markedly lower than that of ¹⁸F-FDG. Conclusion: The sensitive tumor accumulation of ³H-TPP with less propensity for inflammatory regions warrants further investigation of radiolabeled phosphonium analogs for tumor imaging in living subjects.

Key Words: mitochondrial membrane potential • tetraphenylphosphonium • FDG • PET

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