Theranostic agents should ideally be renally cleared and biodegradable. Here, we report the synthesis, characterization and theranostic applications of fluorescent ultrasmall gold quantum clusters that are stabilized by the milk metalloprotein alpha-lactalbumin. We synthesized three types of these nanoprobes that together display fluorescence across the visible and near-infrared spectra when excited at a single wavelength through optical colour coding. In live tumour-bearing mice, the near-infrared nanoprobe generates contrast for fluorescence, X-ray computed tomography and magnetic resonance imaging, and exhibits long circulation times, low accumulation in the reticuloendothelial system, sustained tumour retention, insignificant toxicity and renal clearance. An intravenously administrated near-infrared nanoprobe with a large Stokes shift facilitated the detection and image-guided resection of breast tumours in vivo using a smartphone with modified optics. Moreover, the partially unfolded structure of alpha-lactalbumin in the nanoprobe helps with the formation of an anti-cancer lipoprotein complex with oleic acid that triggers the inhibition of the MAPK and PI3K–AKT pathways, immunogenic cell death and the recruitment of infiltrating macrophages. The biodegradability and safety profile of the nanoprobes make them suitable for the systemic detection and localized treatment of cancer.
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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 too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request.
The custom R code for the bioinformatics is available at https://github.com/wangtaifr/Kircher2020.
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We thank Agropur Ingredients for providing the high-purity bovine α-LA samples used in the study. We acknowledge the staff at the following core facilities at Memorial Sloan Kettering Cancer Center (MSKCC): the Molecular Cytology Core, Small Animal Imaging Core Facility, Electron Microscopy Core, Flow Cytometry Core, NMR Analytical Core and Microchemistry and Proteomics Core. We also thank C. LeKaye and D. Winkleman at the MSKCC MRI core facilities, C.-G. Lee and J. Jimenez of the CLC Imaging Core at Weill Cornell Medical College, C. Adura at the High Throughput and Spectroscopy Resource Center of Rockefeller University for their technical support; current and former Kircher lab members for helpful discussions and critical reading of the manuscript; staff at the Functional Proteomics RPPA Core facility at MD Anderson Cancer Center and M. Wlodarczyk from Brooklyn College at the City University of New York for carrying out atomic absorption spectroscopy; and W. Zhang from the University of Wisconsin-Madison for helping with the schematic figures. The following funding sources to M.F.K. are acknowledged: NIH (nos. R01 EB017748, R01 CA222836 and K08 CA16396); Dana-Farber Innovations Research Fund (IRF); Parker Institute for Cancer Immunotherapy; Pershing Square Sohn Prize by the Pershing Square Sohn Cancer Research Alliance. M.F.K. is a Damon Runyon-Rachleff Innovator who was supported (in part) by the Damon Runyon Cancer Research Foundation (no. DRR-29-14), and the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of MSKCC. We also acknowledge the grant-funding support provided by the MSKCC NIH Core Grant (no. P30-CA008748) and NIH Prostate SPORE (no. P50-CA92629). G.C. is supported by the NIH (nos. R01 CA172546, P01 CA186866 and P50 CA86438) and the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of MSKCC. T.W. is supported by the Lymphoma Research Foundation. The Functional Proteomics RPPA Core at MD Anderson Cancer Center is supported a NIH Support Grant (no. P30 CA016672-40).The National Natural Science Foundation of China (no. 31971311) to L.Z. are also acknowledged. .
J.Y. and M.F.K. have filed a pending patent application related to this work.
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Supplementary figures and references.
Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with AuQC705–BAMLET.
Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with PBS.
Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with AuQC705.
Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with α-LA.
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Yang, J., Wang, T., Zhao, L. et al. Gold/alpha-lactalbumin nanoprobes for the imaging and treatment of breast cancer. Nat Biomed Eng 4, 686–703 (2020). https://doi.org/10.1038/s41551-020-0584-z