Gold/alpha-lactalbumin nanoprobes for the imaging and treatment of breast cancer

Abstract

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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Fig. 1: Concept of renally clearable AuQC705 for cancer imaging.
Fig. 2: Characterization of AuQCs.
Fig. 3: The predominant endocytic trafficking pathway of AuQC705 in MDA-MB-231 human breast cancer cells and tumours is macropinocytosis.
Fig. 4: AuQC705 for imaging breast cancer cells and tumours in living mice.
Fig. 5: PDX model imaging, pharmacokinetics, renal clearance and biodistribution of AuQC705.
Fig. 6: AuQC705–BAMLET is a potent nanocomplex for inducing cancer cell death.
Fig. 7: Molecular mechanisms of anti-cancer AuQC705–BAMLET lipoprotein nanocomplex.

Data availability

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.

Code availability

The custom R code for the bioinformatics is available at https://github.com/wangtaifr/Kircher2020.

References

  1. 1.

    Tang, S. S. K. et al. Current margin practice and effect on re-excision rates following the publication of the SSO-ASTRO consensus and ABS consensus guidelines: a national prospective study of 2858 women undergoing breast-conserving therapy in the UK and Ireland. Eur. J. Cancer 84, 315–324 (2017).

    Google Scholar 

  2. 2.

    Kircher, M. F. et al. A brain tumour molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat. Med. 18, 829–834 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Dawidczyk, C. M. et al. State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J. Control. Release 187, 133–144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zhang, X. D. et al. Ultrasmall Au10–12(SG)10–12 nanomolecules for high tumour specificity and cancer radiotherapy. Adv. Mater. 26, 4565–4568 (2014).

    CAS  Google Scholar 

  5. 5.

    Qin, W., Lohrman, J. & Ren, S. Q. Magnetic and optoelectronic properties of gold nanocluster-thiophene assembly. Angew. Chem. Int. Ed. 53, 7316–7319 (2014).

    CAS  Google Scholar 

  6. 6.

    Hembury, M. et al. Gold-silica quantum rattles for multimodal imaging and therapy. Proc. Natl Acad. Sci. USA 112, 1959–1964 (2015).

    CAS  Google Scholar 

  7. 7.

    Xue, S. H. et al. Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc. Natl Acad. Sci. USA 112, 6607–6612 (2015).

    CAS  Google Scholar 

  8. 8.

    Vishnu, P. & Roy, V. Safety and efficacy of nab-paclitaxel in the treatment of patients with breast cancer. Breast Cancer 5, 53–65 (2011).

    CAS  Google Scholar 

  9. 9.

    Zhao, M. Z. et al. Quantitative proteomic analysis of cellular resistance to the nanoparticle abraxane. ACS Nano 9, 10099–10112 (2015).

    CAS  Google Scholar 

  10. 10.

    Cullis, J. et al. Macropinocytosis of nab-paclitaxel drives macrophage activation in pancreatic cancer. Cancer Immunol. Res. 5, 182–190 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Svensson, M., Hakansson, A., Mossberg, A. K., Linse, S. & Svanborg, C. Conversion of α-lactalbumin to a protein inducing apoptosis. Proc. Natl Acad. Sci. USA 97, 4221–4226 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Murakami, K., Andree, P. J. & Berliner, L. J. Metal ion binding to α-lactalbumin species. Biochemistry 21, 5488–5494 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Nitta, K. & Sugai, S. The evolution of lysozyme and α-lactalbumin. Eur. J. Biochem. 182, 111–118 (1989).

    CAS  Google Scholar 

  14. 14.

    Wei, H. et al. Time-dependent, protein-directed growth of gold nanoparticles within a single crystal of lysozyme. Nat. Nanotechnol. 6, 93–97 (2011).

    CAS  Google Scholar 

  15. 15.

    Davis, A. M., Harris, B. J., Lien, E. L., Pramuk, K. & Trabulsi, J. α-Lactalbumin-rich infant formula fed to healthy term infants in a multicenter study: plasma essential amino acids and gastrointestinal tolerance. Eur. J. Clin. Nutr. 62, 1294–1301 (2008).

    CAS  Google Scholar 

  16. 16.

    Amitay, E. L. & Keinan-Boker, L. Breastfeeding and childhood leukemia incidence: a meta-analysis and systematic review. JAMA Pediatr. 169, e151025 (2015).

    Google Scholar 

  17. 17.

    Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360, 187–195 (2002).

  18. 18.

    Jaini, R. et al. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat. Med. 16, 799–803 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Mossberg, A. K. et al. Bladder cancers respond to intravesical instillation of HAMLET (human α-lactalbumin made lethal to tumour cells). Int. J. Cancer 121, 1352–1359 (2007).

    CAS  Google Scholar 

  20. 20.

    Gustafsson, L., Leijonhufvud, I., Aronsson, A., Mossberg, A. & Svanborg, C. Treatment of skin papillomas with topical α-lactalbumin-oleic acid. N. Engl. J. Med. 350, 2663–2672 (2004).

    CAS  Google Scholar 

  21. 21.

    Rosen, L. S., Ashurst, H. L. & Chap, L. Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. Oncologist 15, 216–235 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wang, Q. et al. Low toxicity and long circulation time of polyampholyte-coated magnetic nanoparticles for blood pool contrast agents. Sci. Rep. 5, 7774 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Wu, Z. K. & Jin, R. C. On the ligand’s role in the fluorescence of gold nanoclusters. Nano Lett. 10, 2568–2573 (2010).

    CAS  Google Scholar 

  24. 24.

    Duconseille, A., Astruc, T., Quintana, N., Meersman, F. & Sante-Lhoutellier, V. Gelatin structure and composition linked to hard capsule dissolution: a review. Food Hydrocoll. 43, 360–376 (2015).

    CAS  Google Scholar 

  25. 25.

    Poole, L. B. The basics of thiols and cysteines in redox biology and chemistry. Free Radic. Biol. Med. 80, 148–157 (2015).

    CAS  Google Scholar 

  26. 26.

    Chaudhuri, A. et al. Protein-dependent membrane interaction of a partially disordered protein complex with oleic acid: implications for cancer lipidomics. Sci. Rep. 6, 35015 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Svensson, M. et al. α-Lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human alpha-lactalbumin made lethal to tumour cells). Protein Sci. 12, 2794–2804 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Schmidbaur, H. The aurophilicity phenomenon: a decade of experimental findings, theoretical concepts and emerging applications. Gold Bull. 33, 3–10 (2000).

    CAS  Google Scholar 

  29. 29.

    Huang, K. Y. et al. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumours in vivo. ACS Nano 6, 4483–4493 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ha, K. D., Bidlingmaier, S. M. & Liu, B. Macropinocytosis exploitation by cancers and cancer therapeutics. Front. Physiol. 7, 381 (2016).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Palm, W. et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ali, S. et al. Increased Ras GTPase activity is regulated by miRNAs that can be attenuated by CDF treatment in pancreatic cancer cells. Cancer Lett. 319, 173–181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Salloum, D., Mukhopadhyay, S., Tung, K., Polonetskaya, A. & Foster, D. A. Mutant ras elevates dependence on serum lipids and creates a synthetic lethality for rapamycin. Mol. Cancer Ther. 13, 733–741 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Huang, J. L. et al. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis. Nat. Commun. 8, 15144 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kerr, M. C. et al. Visualisation of macropinosome maturation by the recruitment of sorting nexins. J. Cell Sci. 119, 3967–3980 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Cheng, Z. et al. Near-infrared fluorescent deoxyglucose analogue for tumour optical imaging in cell culture and living mice. Bioconjug. Chem. 17, 662–669 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Grover-McKay, M., Walsh, S. A., Seftor, E. A., Thomas, P. A. & Hendrix, M. J. Role for glucose transporter 1 protein in human breast cancer. Pathol. Oncol. Res. 4, 115–120 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Whittle, J. R., Lewis, M. T., Lindeman, G. J. & Visvader, J. E. Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res. 17, 17 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Savci-Heijink, C. D. et al. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res. Treat. 150, 547–557 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Hu, W. et al. Protein corona-mediated mitigation of cytotoxicity of graphene oxide. ACS Nano 5, 3693–3700 (2011).

    CAS  Google Scholar 

  41. 41.

    Schneditz, D., Haditsch, B., Jantscher, A., Ribitsch, W. & Krisper, P. Absolute blood volume and hepatosplanchnic blood flow measured by indocyanine green kinetics during hemodialysis. ASAIO J. 60, 452–458 (2014).

    CAS  Google Scholar 

  42. 42.

    Ruggiero, A. et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107, 12369–12374 (2010).

    CAS  Google Scholar 

  43. 43.

    Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kamijima, T. et al. Heat-treatment method for producing fatty acid-bound α-lactalbumin that induces tumour cell death. Biochem. Biophys. Res. Commun. 376, 211–214 (2008).

    CAS  Google Scholar 

  45. 45.

    Rath, E. M., Duff, A. P., Hakansson, A. P., Knott, R. B. & Church, W. B. Small-angle X-ray scattering of BAMLET at pH 12: a complex of α-lactalbumin and oleic acid. Proteins 82, 1400–1408 (2014).

    CAS  Google Scholar 

  46. 46.

    Liu, D., Zhou, P., Liu, X. & Labuza, T. P. Moisture-induced aggregation of alpha-lactalbumin: effects of temperature, cations, and pH. J. Food Sci. 76, C817–C823 (2011).

    CAS  Google Scholar 

  47. 47.

    Permyakov, S. E. et al. A novel method for preparation of HAMLET-like protein complexes. Biochimie 93, 1495–1501 (2011).

    CAS  Google Scholar 

  48. 48.

    Balvan, J. et al. Multimodal holographic microscopy: distinction between apoptosis and oncosis. PLoS ONE 10, e0121674 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Storm, P. et al. Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis. Oncogene 30, 4765–4779 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ho, J. C. S., Nadeem, A., Rydstrom, A., Puthia, M. & Svanborg, C. Targeting of nucleotide-binding proteins by HAMLET—a conserved tumour cell death mechanism. Oncogene 35, 897–907 (2016).

    CAS  Google Scholar 

  51. 51.

    Chu, I. M. et al. Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFβ. PLoS ONE 8, e61125 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Deckers, M. et al. The tumour suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 66, 2202–2209 (2006).

    CAS  Google Scholar 

  53. 53.

    Morrow, K. A. et al. Loss of tumour suppressor Merlin in advanced breast cancer is due to post-translational regulation. J. Biol. Chem. 286, 40376–40385 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Bockbrader, K. M., Tan, M. & Sun, Y. A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene 24, 7381–7388 (2005).

    CAS  Google Scholar 

  55. 55.

    Hodgson, M. C. et al. INPP4B suppresses prostate cancer cell invasion. Cell Commun. Signal. 12, 61 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Zhang, X. et al. Notch3 inhibits epithelial-mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells. Oncogenesis 5, e269 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Bhat, A. A. et al. Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumourigenesis. Oncogene 34, 4570–4580 (2015).

    CAS  Google Scholar 

  58. 58.

    Garg, R. et al. Protein kinase C and cancer: what we know and what we do not. Oncogene 33, 5225–5237 (2014).

    CAS  Google Scholar 

  59. 59.

    Plotkin, L. I., Manolagas, S. C. & Bellido, T. Transduction of cell survival signals by connexin-43 hemichannels. J. Biol. Chem. 277, 8648–8657 (2002).

    CAS  Google Scholar 

  60. 60.

    Li, S. et al. Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release. J. Biol. Chem. 278, 3015–3022 (2003).

    CAS  Google Scholar 

  61. 61.

    Ríos, M. et al. AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors. Cancer Res. 73, 2628–2638 (2013).

    Google Scholar 

  62. 62.

    Liang, J. et al. Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res. 27, 329–351 (2017).

    CAS  Google Scholar 

  63. 63.

    Walsh, L. A. et al. An integrated systems biology approach identifies TRIM25 as a key determinant of breast cancer metastasis. Cell Rep. 20, 1623–1640 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Tekedereli, I. et al. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumours to doxorubicin in an orthotopic model of breast cancer. PLoS ONE 7, e41171 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ahmed, S. U. & Milner, J. Basal cancer cell survival involves JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network. PLoS ONE 4, e7305 (2009).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Song, Q. et al. YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation. PLoS ONE 10, e0120790 (2015).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Smith, G. C., d’Adda di Fagagna, F., Lakin, N. D. & Jackson, S. P. Cleavage and inactivation of ATM during apoptosis. Mol. Cell. Biol. 19, 6076–6084 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Fu, K. et al. DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. Oncogene 31, 1311–1322 (2012).

    CAS  Google Scholar 

  69. 69.

    Yellen, P. et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 10, 3948–3956 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Masters, S. C. & Fu, H. 14-3-3 proteins mediate an essential anti-apoptotic signal. J. Biol. Chem. 276, 45193–45200 (2001).

    CAS  Google Scholar 

  71. 71.

    Chen, L. et al. Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Res. 69, 8853–8861 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Tafolla, E., Wang, S., Wong, B., Leong, J. & Kapila, Y. L. JNK1 and JNK2 oppositely regulate p53 in signaling linked to apoptosis triggered by an altered fibronectin matrix: JNK links FAK and p53. J. Biol. Chem. 280, 19992–19999 (2005).

    CAS  Google Scholar 

  73. 73.

    Yamamoto, Y. & Gaynor, R. B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107, 135–142 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Naidu, S., Wijayanti, N., Santoso, S., Kietzmann, T. & Immenschuh, S. An atypical NF-κB-regulated pathway mediates phorbol ester-dependent heme oxygenase-1 gene activation in monocytes. J. Immunol. 181, 4113–4123 (2008).

    CAS  Google Scholar 

  75. 75.

    Russo, P., Arzani, D., Trombino, S. & Falugi, C. c-myc down-regulation induces apoptosis in human cancer cell lines exposed to RPR-115135 (C31H29NO4), a non-peptidomimetic farnesyltransferase inhibitor. J. Pharmacol. Exp. Ther. 304, 37–47 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Le Mellay, V., Troppmair, J., Benz, R. & Rapp, U. R. Negative regulation of mitochondrial VDAC channels by C-Raf kinase. BMC Cell Biol. 3, 14 (2002).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Wong, C. W., Seow, H. F., Husband, A. J., Regester, G. O. & Watson, D. L. Effects of purified bovine whey factors on cellular immune functions in ruminants. Vet. Immunol. Immunopathol. 56, 85–96 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Kim, S. E. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat. Nanotechnol. 11, 977–985 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Ohkuri, T. et al. A protein’s conformational stability is an immunologically dominant factor: evidence that free-energy barriers for protein unfolding limit the immunogenicity of foreign proteins. J. Immunol. 185, 4199–4205 (2010).

    CAS  Google Scholar 

  81. 81.

    Xie, J., Zheng, Y. & Ying, J. Y. Protein-directed synthesis of highly fluorescent gold nanoclusters. J. Am. Chem. Soc. 131, 888–889 (2009).

    CAS  Google Scholar 

  82. 82.

    Pfeil, W. Is thermally denatured protein unfolded? The example of alpha-lactalbumin. Biochim. Biophys. Acta 911, 114–116 (1987).

    CAS  Google Scholar 

  83. 83.

    Duff, D. G., Baiker, A. & Edwards, P. P. A new hydrosol of gold clusters. 1. Formation and particle size variation. Langmuir 9, 2301–2309 (1993).

    CAS  Google Scholar 

  84. 84.

    Micsonai, A. et al. Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy. Proc. Natl Acad. Sci. USA 112, E3095–E3103 (2015).

    CAS  Google Scholar 

  85. 85.

    Eaton, D. F. International union of pure and applied chemistry organic chemistry division commission on photochemistry. Reference materials for fluorescence measurement. J. Photochem. Photobiol. B 2, 523–531 (1988).

    CAS  Google Scholar 

  86. 86.

    Marques, M. R. C., Loebenberg, R. & Almukainzi, M. Simulated biological fluids with possible application in dissolution testing. Dissolut. Technol. 18, 15–28 (2011).

    CAS  Google Scholar 

  87. 87.

    Liskova, K., Kelly, A. L., O’Brien, N. & Brodkorb, A. Effect of denaturation of α-lactalbumin on the formation of BAMLET (bovine α-lactalbumin made lethal to tumour cells). J. Agric. Food Chem. 58, 4421–4427 (2010).

    CAS  Google Scholar 

  88. 88.

    Wawrik, B. & Harriman, B. H. Rapid, colourimetric quantification of lipid from algal cultures. J. Microbiol. Methods 80, 262–266 (2010).

    CAS  Google Scholar 

  89. 89.

    Ashburner, M. et al. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    UniProt Consortium. UniProt: a hub for protein information. Nucleic Acids Res. 43, D204–D212 (2015).

  91. 91.

    Martijn, T & Ellis, P. Treemap: treemap visualization. Treemap v2.4-2 (Martijn, T., 2017); https://cran.r-project.org/web/packages/treemap/index.html

  92. 92.

    Martin, M., Seth, F. & Robert, G. GSEABase: gene set enrichment data structures and methods. GSEABase v1.5 (Bioconductor Package Maintainer, 2016); https://bioconductor.org/packages/release/bioc/html/GSEABase.html

  93. 93.

    Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Nioka, S. et al. Simulation study of breast tissue hemodynamics during pressure perturbation. Adv. Exp. Med. Biol. 566, 17–22 (2005).

    Google Scholar 

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Acknowledgements

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. .

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J.Y. and M.F.K. conceived and designed the experiments and co-wrote the manuscript. J.Y. synthesized and characterized AuQCs. Schematic atomic structures of AuQCs were provided by L.Z. Animal studies were performed by J.Y., V.K.R., H.H., H.Z., R.H. and J.H.H. MALDI was performed by R.C.H. and M.M.M. Pathway analysis was conducted by T.W. and G.C., and biochemical studies were run by S.J.; M.B.B. took AFM images and HPLC was performed by W.P.; J.Y., T.W., S.J., C.A., S.P., I.J.C., J.H.H., G.C. and M.F.K. analysed data. The project was supervised by M.F.K. and the manuscript was reviewed and approved by all of the authors.

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Correspondence to Moritz F. Kircher.

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J.Y. and M.F.K. have filed a pending patent application related to this work.

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Reporting Summary

Supplementary Video 1

Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with AuQC705–BAMLET.

Supplementary Video 2

Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with PBS.

Supplementary Video 3

Time-lapse DIC microscopy imaging of MDA-MB-231 cancer cells treated with AuQC705.

Supplementary Video 4

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

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