Abstract
Carbonic anhydrase IX (CAIX) is a cancer-associated molecular target for several classes of therapeutics. CAIX is overexpressed in a large fraction of renal cell carcinomas (RCC). Radionuclide molecular imaging of CAIX-expression might offer a non-invasive methodology for stratification of patients with disseminated RCC for CAIX-targeting therapeutics. Radiolabeled monoclonal antibodies and their fragments are actively investigated for imaging of CAIX expression. Promising alternatives are small non-immunoglobulin scaffold proteins, such as affibody molecules. A CAIX-targeting affibody ZCAIX:2 was re-designed with the aim to decrease off-target interactions and increase imaging contrast. The new tracer, DOTA-HE3-ZCAIX:2, was labeled with 111In and characterized in vitro. Tumor-targeting properties of [111In]In-DOTA-HE3-ZCAIX:2 were compared head-to-head with properties of the parental variant, [99mTc]Tc(CO)3-HE3-ZCAIX:2, and the most promising antibody fragment-based tracer, [111In]In-DTPA-G250(Fab’)2, in the same batch of nude mice bearing CAIX-expressing RCC xenografts. Compared to the 99mTc-labeled parental variant, [111In]In-DOTA-HE3-ZCAIX:2 provides significantly higher tumor-to-lung, tumor-to-bone and tumor-to-liver ratios, which is essential for imaging of CAIX expression in the major metastatic sites of RCC. [111In]In-DOTA-HE3-ZCAIX:2 offers significantly higher tumor-to-organ ratios compared with [111In]In-G250(Fab’)2. In conclusion, [111In]In-DOTA-HE3-ZCAIX:2 can be considered as a highly promising tracer for imaging of CAIX expression in RCC metastases based on our results and literature data.
Highlights
Targeting of gene products that are aberrantly expressed in cancer has refined treatment of disseminated cancers by increasing efficacy and reducing toxicity to normal tissues
Radionuclide molecular imaging of carbonic anhydrase IX (CAIX)-expression might offer a non-invasive methodology for stratification of patients with disseminated renal cell carcinomas (RCC) for CAIX-targeting therapeutics. It might be useful for other applications, such as vascular endothelial growth factor (VEGF)-targeted therapy, where response to sorafenib therapy correlates with CAIX-expression level[19]
The goal of this study was to perform a direct comparison of imaging properties of the newly designed radiolabeled DOTA-ZCAIX:[2] with the currently best available imaging probes, [99mTc]Tc(CO)3-HE3-ZCAIX:[2] and [111In]In-DTPA-G250(Fab’)[2], to select the best variant for detection of CAIX expression in disseminated renal cell carcinoma
Summary
Targeting of gene products that are aberrantly expressed (e.g. overexpressed) in cancer has refined treatment of disseminated cancers by increasing efficacy and reducing toxicity to normal tissues. HIF1α is not hydroxylated and www.nature.com/scientificreports it cannot be recognized by pVHL and starts accumulating in the cell This results in overexpression of CAIX in hypoxic tumor areas[6]. Radionuclide molecular imaging of CAIX-expression might offer a non-invasive methodology for stratification of patients with disseminated RCC for CAIX-targeting therapeutics It might be useful for other applications, such as vascular endothelial growth factor (VEGF)-targeted therapy, where response to sorafenib therapy correlates with CAIX-expression level[19]. Radiolabeled (Fab’)[2] fragments of cG250 (G250(Fab’)2) have been evaluated in tumor-bearing mice and shown to be a promising tracer for imaging of hypoxia-related CAIX expression in head-and-neck tumors[30,31,32]. This probe provided an optimal imaging already at 24 h after injection
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