Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.
The family of iodido OsII arene phenylazopyridine complexes [Os(η6‐p‐cym)(5‐R1‐pyridylazo‐4‐R2‐phenyl))I]+ (where p‐cym=para‐cymene) exhibit potent sub‐micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I− ligand in the presence of glutathione (GSH). The X‐ray crystal structures of two active complexes are reported, 1‐I (R1=OEt, R2=H) and 2‐I (R1=H, R2=NMe2). They were labelled with the radionuclide 131I (β−/γ emitter, t1/2 8.02 d), and their activity in MCF‐7 human breast cancer cells was studied. 1‐[131I] and 2‐[131I] exhibit good stability in both phosphate‐buffered saline and blood serum. In contrast, once taken up by MCF‐7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo‐osmium complexes.
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