Simultaneous proteoglycans and hypoxia mapping of chondrosarcoma environment by frequency selective CEST MRI

Purpose: To evaluate the relevance of CEST frequency selectivity in simultaneous in vivo imaging of both of chondrosarcoma's phenotypic features, that are, its high proteoglycan concentration and its hypoxic core. Methods: Swarm rat chondrosarcomas were implanted subcutaneously in NMRI nude mice. When tumors were measurable (12-16 days postoperative), mice were submitted to GAG, guanidyl, and APT CEST imaging. Proteoglycans and hypoxia were assessed in parallel by nuclear imaging exploiting Tc-99m-NTP 15-5 and F-18-FMISO, respectively. Data were completed by ex vivo analysis of proteoglycans (histology and biochemical assay) and hypoxia (immunofluorescence). Results: Quantitative analysis of GAG CEST evidenced a significantly higher signal for tumor tissues than for muscles. These results were in agreement with nuclear imaging and ex vivo data. For imaging tumoral pH in vivo, the CEST ratio of APT/guanidyl was studied. This highlighted an important heterogeneity inside the tumor. The hypoxic status was confirmed by F-18-FMISO PET imaging and ex vivo immunofluorescence. Conclusion: CEST MRI simultaneously imaged both chondrosarcoma properties during a single experimental run and without the injection of any contrast agent. Both MR and nuclear imaging as well as ex vivo data were in agreement and showed that this chondrosarcoma animal model was rich in proteoglycans. However, even if tumors were lightly hypoxic at the stage studied, acidic areas were highlighted and mapped inside the tumor.