Abstract
Introduction Hypoxia-induced ανβ3 integrin and aminopeptidase N (APN/CD13) receptor expression play an important role in tumor neoangiogenesis. APN/CD13-specific 68Ga-NOTA-c(NGR), ανβ3 integrin-specific 68Ga-NODAGA-[c(RGD)]2, and hypoxia-specific 68Ga-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 68Ga-NOTA-c(NGR) and 68Ga-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 × 106 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 68Ga-NOTA-c(NGR) or 68Ga-NODAGA-[c(RGD)]2 (as angiogenesis tracers) or 68Ga-DOTA-nitroimidazole (for hypoxia imaging), whole-body PET/MRI scans were performed. Results Hypoxic regions and angiogenic markers (αvβ3 integrin and APN/CD13) were determined using 68Ga-NOTA-c(NGR), 68Ga-DOTA-nitroimidazole, and 68Ga-NODAGA-[c(RGD)]2 in subcutaneously growing He/De tumors in rats. 68Ga-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 68Ga-DOTA-nitroimidazole and 68Ga-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.
Highlights
Hypoxia-induced ανβ3 integrin and aminopeptidase N (APN/CD13) receptor expression play an important role in tumor neoangiogenesis
The aim of this study was to evaluate whether 68Ga-NOTA-c(NGR) and 68Ga-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
By analyzing the accumulation of 68Ga-NOTAc(NGR) in the whole tumor, we found that the SUVmean and SUVmax values of the He/De tumors were 0:42 ± 0:04 and 1:79 ± 0:15, respectively (Figure 1(d))
Summary
Hypoxia-induced ανβ integrin and aminopeptidase N (APN/CD13) receptor expression play an important role in tumor neoangiogenesis. APN/CD13-specific 68Ga-NOTA-c(NGR), ανβ integrin-specific 68Ga-NODAGA-[c(RGD)]2, and hypoxia-specific 68Ga-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. Hypoxic regions and angiogenic markers (αvβ integrin and APN/CD13) were determined using 68Ga-NOTAc(NGR), 68Ga-DOTA-nitroimidazole, and 68Ga-NODAGA-[c(RGD)]2 in subcutaneously growing He/De tumors in rats. Aminopeptidase N (CD13) is a zinc-dependent transmembrane exopeptidase [14] It can be found in high expression on several tumor cells, for example, melanoma and prostate, ovarian, renal, colon, and pancreas cancers, on the endothelial cell surface [15,16,17]. It plays an important role in angiogenesis and enzyme-catalysed degradation of the extracellular matrix, which facilitates the tumor cell invasion through the blood stream, hereby causing metastasis formation [18, 19]
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