title: Molecular Imaging of Tumor Hypoxia: Existing Problems and Their Potential Model-Based Solutions.
abstract: Molecular imaging of tissue hypoxia generates contrast in hypoxic areas by applying hypoxia-specific tracers in organisms. In cancer tissue, the injected tracer needs to be transported over relatively long distances and accumulates slowly in hypoxic regions. Thus, the signal-to-background ratio of hypoxia imaging is very small and a non-specific accumulation may suppress the real hypoxia-specific signals. In addition, the heterogeneous tumor microenvironment makes the assessment of the tissue oxygenation status more challenging. In this study, the diffusion potential of oxygen and of a hypoxia tracer for 4 different hypoxia subtypes: ischemic acute hypoxia, hypoxemic acute hypoxia, diffusion-limited chronic hypoxia and anemic chronic hypoxia are theoretically assessed. In particular, a reaction-diffusion equation is introduced to quantitatively analyze the interstitial diffusion of the hypoxia tracer [(18)F]FMISO. Imaging analysis strategies are explored based on reaction-diffusion simulations. For hypoxia imaging of low signal-to-background ratio, pharmacokinetic modelling has advantages to extract underlying specific binding signals from non-specific background signals and to improve the assessment of tumor oxygenation. Different pharmacokinetic models are evaluated for the analysis of the hypoxia tracer [(18)F]FMISO and optimal analysis model were identified accordingly. The improvements by model-based methods for the estimation of tumor oxygenation are in agreement with experimental data. The computational modelling offers a tool to explore molecular imaging of hypoxia and pharmacokinetic modelling is encouraged to be employed in the corresponding data analysis.
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany. k.shi@tum.de.
authors.forename: Kuangyu
authors.initials: K
authors.lastname: Shi
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany.
authors.forename: Sibylle I
authors.initials: SI
authors.lastname: Ziegler
authors.affiliation: Department Radiooncology and Radiotherapy, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D003198:Computer Simulation; D003287:Contrast Media / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004058:Diffusion; D006801:Humans; D008833:Microcirculation; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008954:Models, Biological; D057054:Molecular Imaging / Q000295:instrumentation / Q000379:methods*; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism*; D019047:Phantoms, Imaging; D059629:Signal-To-Noise Ratio; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; C031843:fluoromisonidazole; D008920:Misonidazole; D010100:Oxygen
keywords: Molecular imaging; Pharmacokinetic modelling; Simulation of hypoxia imaging; Tumor hypoxia