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Hypoxia-induced  α   ν   β  3  integrin and aminopeptidase N (APN/CD13) receptor expression play an important role in tumor neoangiogenesis. APN/CD13-specific  68 Ga-NOTA-c(NGR),  α   ν   β  3  integrin-specific  68 Ga-NODAGA-[c(RGD)] 2 , and hypoxia-specific  68 Ga-DOTA-nitroimidazole enable the  in vivo  detection of the neoangiogenic process and the hypoxic regions in the tumor mass using positron emission tomography (PET) imaging. The aim of this study was to evaluate whether  68 Ga-NOTA-c(NGR) and  68 Ga-DOTA-nitroimidazole allow the  in vivo  noninvasive detection of the temporal changes of APN/CD13 expression and hypoxia in experimental He/De tumors using positron emission tomography.Materials and Methods   5 × 10 6  hepatocellular carcinoma (He/De) cells were used for the induction of a subcutaneous tumor model in Fischer-344 rats. He/De tumor-bearing animals were anaesthetized, and 90 min after intravenous injection of 10.2 ± 1.1 MBq  68 Ga-NOTA-c(NGR) or  68 Ga-NODAGA-[c(RGD)] 2  (as angiogenesis tracers) or  68 Ga-DOTA-nitroimidazole (for hypoxia imaging), whole-body PET/MRI scans were performed.Results   Hypoxic regions and angiogenic markers ( α  v  β  3  integrin and APN/CD13) were determined using  68 Ga-NOTA-c(NGR),  68 Ga-DOTA-nitroimidazole, and  68 Ga-NODAGA-[c(RGD)] 2  in subcutaneously growing He/De tumors in rats.  68 Ga-NOTA-c(NGR) showed the strong APN/CD13 positivity of He/De tumors  in vivo , by which observation was confirmed by western blot analysis. By the qualitative analysis of PET images, heterogenous accumulation was found inside He/De tumors using all radiotracers. Significantly ( p  ≤ 0.01) higher SUVmean and SUVmax values were found in the radiotracer avid regions of the tumors than those of the nonavid areas using hypoxia and angiogenesis-specific radiopharmaceuticals. Furthermore, a strong correlation was found between the presence of angiogenic markers, the appearance of hypoxic regions, and the tumor volume using noninvasive  in vivo  PET imaging.Conclusion    68 Ga-DOTA-nitroimidazole and  68 Ga-NOTA-c(NGR) are suitable diagnostic radiotracers for the detection of the temporal changes of hypoxic areas and neoangiogenic molecule (CD13) expression, which vary during tumor growth in a hepatocellular carcinoma model.

biomed research international

<i>In Vivo</i> Imaging of Hypoxia and Neoangiogenesis in Experimental Syngeneic Hepatocellular Carcinoma Tumor Model Using Positron Emission Tomography

In Vivo Imaging of Hypoxia and Neoangiogenesis in Experimental Syngeneic Hepatocellular Carcinoma Tumor Model Using Positron Emission Tomography