Owing to the diversity of cancer types and the spatiotemporal heterogeneity of tumour signals, high-resolution imaging of occult malignancy is challenging. 18F-fluorodeoxyglucose positron emission tomography allows for near-universal cancer detection, yet in many clinical scenarios it is hampered by false positives. Here, we report a method for the amplification of imaging contrast in tumours via the temporal integration of the imaging signals triggered by tumour acidosis. This method exploits the catastrophic disassembly, at the acidic pH of the tumour milieu, of pH-sensitive positron-emitting neutral copolymer micelles into polycationic polymers, which are then internalized and retained by the cancer cells. Positron emission tomography imaging of the 64Cu-labelled polymers detected small occult tumours (10–20 mm3) in the brain, head, neck and breast of mice at much higher contrast than 18F-fluorodeoxyglucose, 11C-methionine and pH-insensitive 64Cu-labelled nanoparticles. We also show that the pH-sensitive probes reduce false positive detection rates in a mouse model of non-cancerous lipopolysaccharide-induced inflammation. This macromolecular strategy for integrating tumour acidosis should enable improved cancer detection, surveillance and staging.
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The authors declare that the main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.
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We thank R. Bachoo for the original 73C cancer cells, Y. Li and Q. Feng for helpful discussions. This work is supported by the National Institutes of Health (R01CA192221 and R01CA211930) and Cancer Prevention and Research Institute of Texas (RP180343). The animal imaging work was supported by a University of Texas Southwestern Small Animal Imaging Resource Grant (U24 CA126608), and radiochemistry and PET imaging were supported by a Simmons Cancer Center Support Grant (P30 CA142543) and CPRIT Grant (RP110771) to X.S.
B.D.S. and J.G. are scientific co-founders and scientific advisors of OncoNano Medicine, Inc. G.Huang is a scientific advisor for OncoNano Medicine, Inc. T.Z. is currently an employee of OncoNano Medicine, Inc.
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Supplementary figures, tables and video captions.
3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 24 h post-injection of 64Cu-UPS6.9.
3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 1 h post-injection of FDG.
3D rotation of the PET/CT imaging of HN5 tumour-bearing mice 24 h post-injection of 64Cu-PEG-PLA.