Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning

Abstract

Tumor hypoxia, present in many human cancers, can lead to resistance to radiation and chemotherapy, is associated with a more aggressive tumor phenotype and is an independent prognostic factor of clinical outcome. It is therefore important to identify and localize tumor hypoxia in cancer patients. In the current study, serial microPET imaging was used to evaluate iodine-124-labeled iodo-azomycin-galactoside ((124)I-IAZG) (4.2-day physical half-life) as a hypoxia imaging agent in 17 MCa breast tumors and six FSaII fibrosarcomas implanted in mice. For comparison, another promising hypoxic-cell PET radiotracer, fluorine-18-labeled fluoro-misonidazole ((18)F-FMISO), was also imaged in the same tumor-bearing animals. Twelve animals were also imaged with (18)F-labeled fluoro-deoxyglucose ((18)F-FDG). In addition, histological examination was performed, and direct measurement of tumor oxygenation status carried out with the Oxylite probe system. Two size groups were used, relatively well-oxygenated tumors in the range of 80-180 mg were designated as small, and those >300 mg and highly hypoxic, as large. Based on the data from 11 MCa and six FSaII tumors, both (124)I-IAZG and (18)F-FMISO images showed high tracer uptake in the large tumors. In (18)F-FMISO images at 1, 3-4, and 6-8 h post-injection (p.i.), there was considerable whole-body background activity. In contrast, (124)I-IAZG imaging was optimal when performed at 24-48 h p.i., when the whole-body background had dissipated considerably. As a result, the (124)I-IAZG images at 24-48 h p.i. had higher tumor to whole-body activity contrast than the (18)F-FMISO images at 3-6 h p.i. Region-of-interest analysis was performed as a function of time p.i. and indicated a tumor uptake of 5-10% (of total-body activity) for FMISO at 3-6 h p.i., and of ~17% for IAZG at 48 h p.i. This was corroborated by biodistribution data in that the tumor-to-normal tissue (T/N, normal tissues of blood, heart, lung, liver, spleen, kidney, intestine, and muscle) activity ratios of IAZG at 24 h p.i. was 1.5-2 times higher than those of FMISO at 3 h p.i., with the exception of stomach. Statistical analysis indicated that these differences in T/N ratios were significant. The small tumors were visualized in the (18)F-FDG images, but not in the (124)I-IAZG or (18)F-FMISO images. This was perhaps due to the combined effect of a smaller tumor volume and a lower hypoxic fraction. Oxylite probe measurement indicated a lesser proportion of regions with pO(2)<2.5 mmHg in the small tumors (e.g., pO(2) was <2.5 mmHg in 28% and 67% of the data in small and large FSaII tumors, respectively), and the biodistribution data showed lower uptake of the tracers in the small tumors than in the large tumors. In the first study of its kind, using serial microPET imaging in conjunction with biodistribution analysis and direct probe measurements of local pO(2) to evaluate tumor hypoxia markers, we have provided data showing the potential of (124)I-IAZG for hypoxia imaging.

Tumor Hypoxia Imaging

“…The former has been radiolabeled with 123 I and used as a single-photon emission computed tomography tracer in clinical trials with promising results (41,42). The latter, 124 Iazomycin-galactoside, has been studied by microPET in rodent models (43). The properties of these compounds have been compared with other 2-nitroimidazoles (e.g., [ 18 F]FMISO) and reviewed by Chapman et al (44).…”

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

“…Somatostatin receptor imaging can also identify and localize metastatic lesions and is thus useful in staging and treatment and surgical planning. In one study, 111 In-labeled pentetreotide altered patient management in 47% of 122 gastrinoma patients (145). Further, as also discussed below, imaging (e.g., using 86 Y-labeled somatostatin analogues; ref.…”

“…However, radiolabeled depreotide (Neotect) also has affinity for subtype 3 and can image tumors expressing these receptors, such as insulinomas. Most (85%) carcinoid neuroendocrine tumors, which have an 80% to 90% incidence of subtype 2A receptors, can be imaged with 111 In-labeled pentetreotide. Somatostatin receptor imaging can also identify and localize metastatic lesions and is thus useful in staging and treatment and surgical planning.…”

“…These example clinical settings include breast cancer, prostate cancer, multidrug resistance, neuroendocrine tumors, and lymphomas. Some of the imaging probes discussed in this section are approved and are used in routine clinical practice to direct cancer therapy (e.g., 111 In-labeled pentetreotide or capromab). As noted in Table 1, many of the others (e.g., 18 F-labeled estrogens or androgens) have been tested in investigational clinical studies but are not currently used to direct therapy.…”

[18F]EF3 is not superior to [18F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model

“…In hypoxic environments, these compounds are subject of a reductive metabolism, which causes the formation of reactive intermediates (nitrose and hydroxylamine) that become covalently bound to macromolecular cellular components [6]. Based on this principle, their selective binding to hypoxic cells has already been demonstrated in vitro as well as in vivo [7][8][9][10].…”