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Extraction, detection, and profiling of serum biomarkers using designed Fe3O4@SiO2@HA core–shell particles

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Abstract

Serum biomarkers in the form of proteins (e.g. cluster of differentiation-44 (CD44)) have been demonstrated to have high clinical sensitivity and specificity for disease diagnosis and prognosis. Owing to the high sample complexity and low molecular abundance in serum, the detection and profiling of biomarkers rely on efficient extraction by materials and devices, mostly using immunoassays via antibody-antigen recognition. Antibody-free approaches are promising and need to be developed for real-case applications in serum to address the limitations of antibody-based techniques in terms of robustness, expense, and throughput. In this work, we demonstrated a novel approach using hyaluronic acid (HA)-modified materials/devices for the extraction, detection, and profiling of serum biomarkers via ligand-protein interactions. We constructed Fe3O4@SiO2@HA particles with different sizes through layer-by-layer assembly and for the first time applied HA-functionalized particles in the facile extraction and sequence identification of CD44 in serum by mass spectrometry. We also first validated HA-CD44 binding through electrochemical sensing using HA-modified electrodes in both standard solutions and diluted serum samples, achieving a detection limit of ∼0.6 ng/mL and a linear response range from 1 ng/mL to 10 μg/mL. Furthermore, we performed profiling of HA-binding serum proteome, providing a new preliminary benchmark for the construction of future databases, and we investigated selected surface chemistries of particles for the capture of proteins in serum. Our work not only resulted in the development of a platform technology for CD44 extraction/detection and HA-binding proteome identification, but also guided the design of ligand affinity-based approaches for antibody-free analysis of serum biomarkers towards diagnostic applications.

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References

  1. Hanash, S. M.; Pitteri, S. J.; Faca, V. M. Mining the plasma proteome for cancer biomarkers. Nature 2008, 452, 571–579.

    Article  Google Scholar 

  2. Kosaka, P. M.; Pini, V.; Ruz, J. J.; da Silva, R. A.; González, M. U.; Ramos, D.; Calleja, M.; Tamayo J. Detection of cancer biomarkers in serum using a hybrid mechanical and optoplasmonic nanosensor. Nat. Nanotechnol. 2014, 9, 1047–1053.

    Article  Google Scholar 

  3. de Gramont, A.; Watson, S.; Ellis, L. M.; Rodón, J.; Tabernero, J.; de Gramont, A.; Hamilton, S. R.Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Nat. Rev. Clin. Oncol. 2015, 12, 197–212.

    Article  Google Scholar 

  4. Vargas, A. J.; Harris, C. C. Biomarker development in the precision medicine era: Lung cancer as a case study. Nat. Rev. Cancer 2016, 16, 525–537.

    Article  Google Scholar 

  5. Wu, L.; Qu, X. G. Cancer biomarker detection: Recent achievements and challenges. Chem. Soc. Rev. 2015, 44, 2963–2997.

    Article  Google Scholar 

  6. Shi, T.; Fillmore, T. L.; Sun, X.; Zhao, R.; Schepmoes, A. A.; Hossain, M.; Xie, F.; Wu, S.; Kim, J. S.; Jones, N. et al. Antibody-free, targeted mass-spectrometric approach for quantification of proteins at low picogram per milliliter levels in human plasma/serum. Proc. Natl. Acad. Sci. USA 2012, 109, 15395–15400.

    Article  Google Scholar 

  7. Liu, B.; Li, Y. L.; Wan, H.; Wang, L.; Xu, W.; Zhu, S. J.; Liang, Y. Y.; Zhang, B.; Lou, J. T.; Dai, H. J. et al. High performance, multiplexed lung cancer biomarker detection on a plasmonic gold chip. Adv. Funct. Mater. 2016, 26, 7994–8002.

    Article  Google Scholar 

  8. Stern, E.; Vacic, A.; Rajan, N. K.; Criscione, J. M.; Park, J.; Ilic, B. R.; Mooney, D. J.; Reed, M. K.; Fahmy, T. M. Label-free biomarker detection from whole blood. Nat. Nanotechnol. 2010, 5, 138–142.

    Article  Google Scholar 

  9. Zöller, M. CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer 2011, 11, 254–267.

    Article  Google Scholar 

  10. Jin, L. Q.; Hope, K. J.; Zhai, Q. L.; Smadja-Joffe, F.; Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 2006, 12, 1167–1174.

    Article  Google Scholar 

  11. Banerji, S.; Wright, A. J.; Noble, M.; Mahoney, D. J.; Campbell, I. D.; Day, A. J.; Jackson, D. G. Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nat. Struct. Mol. Biol. 2007, 14, 234–239.

    Article  Google Scholar 

  12. Sun, X. M.; Wan, J. J.; Kun, Q. Designed micro-devices for in-vitro diagnostics. Small Methods, in press, DOI:10.1002/smtd.201700196.

  13. Misra, S.; Hascall, V. C.; De Giovanni, C.; Markwald, R. R.; Ghatak, S. Delivery of CD44 shRNA/nanoparticles within cancer cells: Perturbation of hyaluronan/CD44v6 interactions and reduction in adenoma growth in Apc min/+ mice. J. Biol. Chem. 2009, 284, 12432–12446.

    Article  Google Scholar 

  14. Wang, S. J.; Tian, Y.; Tian, W.; Sun, J.; Zhao, S.; Liu, Y.; Wang, C. Y.; Tang, Y. X.; Ma, X. Q.; Teng, Z. G. et al. Selectively sensitizing malignant cells to photothermal therapy using a CD44-targeting heat shock protein 72 depletion nanosystem. ACS Nano 2016, 10, 8578–8590.

    Article  Google Scholar 

  15. Wang, Y.; Gu, H. C. Core–shell-type magnetic mesoporous silica nanocomposites for bioimaging and therapeutic agent delivery. Adv. Mater. 2015, 27, 576–585.

    Article  Google Scholar 

  16. Wu, J.; Wei, X.; Gan, J. R.; Huang, L.; Shen, T.; Lou, J. T.; Liu, B. H.; Zhang, J. X. J.; Qian, K. Multifunctional magnetic particles for combined circulating tumor cells isolation and cellular metabolism detection. Adv. Funct. Mater. 2016, 26, 4016–4025.

    Article  Google Scholar 

  17. Li, Y.; Zhang, X. M.; Deng, C. H. Functionalized magnetic nanoparticles for sample preparation in proteomics and peptidomics analysis. Chem. Soc. Rev. 2013, 42, 8517–8539.

    Article  Google Scholar 

  18. Liu, J.; Qiao, S. Z.; Hu, Q. H.; Lu, G. Q. Magnetic nanocomposites with mesoporous structures: Synthesis and applications. Small 2011, 7, 425–443.

    Article  Google Scholar 

  19. Boyjoo, Y.; Wang, M. W.; Pareek, V. K.; Liu, J.; Jaroniec, M. Synthesis and applications of porous non-silica metal oxide submicrospheres. Chem. Soc. Rev. 2016, 45, 6013–6047.

    Article  Google Scholar 

  20. Liu, J.; Wickramaratne, N. P.; Qiao, S. Z.; Jaroniec, M. Molecular-based design and emerging applications of nanoporous carbon spheres. Nat. Mater. 2015, 14, 763–774.

    Article  Google Scholar 

  21. Liu, J.; Qiao, S. Z.; Chen, J. S.; Lou, X. W.; Xing, X. R.; Lu, G. Q. Yolk/shell nanoparticles: New platforms for nanoreactors, drug delivery and lithium-ion batteries. Chem. Commun. 2011, 47, 12578–12591.

    Article  Google Scholar 

  22. Xu, H.; Cui, L. L.; Tong, N. H.; Gu, H. C. Development of high magnetization Fe3O4/polystyrene/silica nanospheres via combined miniemulsion/emulsion polymerization. J. Am. Chem. Soc. 2006, 128, 15582–15583.

    Article  Google Scholar 

  23. Farr, T. D.; Lai, C. H.; Grünstein, D.; Orts-Gil, G.; Wang, C. C.; Boehm-Sturm, P.; Seeberger, P. H.; Harms, C. Imaging early endothelial inflammation following stroke by core shell silica superparamagnetic glyconanoparticles that target selectin. Nano Lett. 2014, 14, 2130–2134.

    Article  Google Scholar 

  24. Ding, H. L.; Zhang, Y. X.; Wang, S.; Xu, J. M.; Xu, S. C.; Li, G. H. Fe3O4@SiO2core/shell nanoparticles: The silica coating regulations with a single core for different core sizes and shell thicknesses. Chem. Mater. 2012, 24, 4572–4580.

    Article  Google Scholar 

  25. Kim, S. H.; Bazin, N.; Shaw, J. I.; Yoo, J. H.; Worsley, M. A.; Satcher, J. H.; Sain, J. D.; Kuntz, J. D.; Kucheyev, S. O.; Baumann, T. F. et al. Synthesis of nanostructured/macroscopic low-density copper foams based on metalcoated polymer core–shell particles. ACS Appl. Mater. Interfaces 2016, 8, 34706–34714.

    Article  Google Scholar 

  26. Zhu, S. B.; Ma, L.; Wang, S.; Chen, C. X.; Zhang, W. Q.; Yang, L. L.; Hang, W.; Nolan, J. P.; Wu, L.; Yan, X. M. Light-scattering detection below the level of single fluorescent molecules for high-resolution characterization of functional nanoparticles. ACS Nano 2014, 8, 10998–11006.

    Article  Google Scholar 

  27. Thissen, P.; Peixoto, T.; Longo, R. C.; Peng, W. N.; Schmidt, W. G.; Cho, K.; Chabal, Y. J. Activation of surface hydroxyl groups by modification of H-terminated Si(111) surfaces. J. Am. Chem. Soc. 2012, 134, 8869–8874.

    Article  Google Scholar 

  28. Liu, X.; Dai, Q.; Austin, L.; Coutts, J.; Knowles, G.; Zou, J. H.; Chen, H.; Huo, Q. A one-step homogeneous immunoassay for cancer biomarker detection using gold nanoparticle probes coupled with dynamic light scattering. J. Am. Chem. Soc. 2008, 130, 2780–2782.

    Article  Google Scholar 

  29. Kralj, S.; Makovec, D. Magnetic assembly of superparamagnetic iron oxide nanoparticle clusters into nanochains and nanobundles. ACS Nano 2015, 9, 9700–9707.

    Article  Google Scholar 

  30. Li, W. P.; Liao, P. Y.; Su, C. H.; Yeh, C. S. Formation of oligonucleotide-gated silica shell-coated Fe3O4-Au core–shell nanotrisoctahedra for magnetically targeted and near-infrared light-responsive theranostic platform. J. Am. Chem. Soc. 2014, 136, 10062–10075.

    Article  Google Scholar 

  31. Hu, M.; Yan, J.; He, Y.; Lu, H. T.; Weng, L. X.; Song, S. P.; Fan, C. H.; Wang, L. H. Ultrasensitive, multiplexed detection of cancer biomarkers directly in serum by using a quantum dot-based microfluidic protein chip. ACS Nano 2010, 4, 488–494.

    Article  Google Scholar 

  32. Yu, M. H.; Jambhrunkar, S.; Thorn, P.; Chen, J. Z.; Gu, W. Y.; Yu, C. Z. Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-over-expressing cancer cells. Nanoscale 2013, 5, 178–183.

    Article  Google Scholar 

  33. Djung, H. S.; Kong, W. H.; Sung, D. K.; Lee, M. Y.; Beack, S. E.; Keum, D. H.; Kim, K. S.; Yun, S. H.; Hahn, S. K. Nanographene oxide–hyaluronic acid conjugate for photothermal ablation therapy of skin cancer. ACS Nano 2014, 8, 260–268.

    Article  Google Scholar 

  34. Shao, M. F.; Ning, F. Y.; Zhao, J. W.; Wei, M.; Evans, D. G.; Duan, X. Preparation of Fe3O4@SiO2@layered double hydroxide core-shell microspheres for magnetic separation of proteins. J. Am. Chem. Soc. 2012, 134, 1071–1077.

    Article  Google Scholar 

  35. Skelton, T. P.; Zeng, C. X.; Nocks, A.; Stamenkovic, I. Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan. J. Cell Biol. 1998, 140, 431–446.

    Article  Google Scholar 

  36. Wang, Y.; Qian, K.; Guo, K.; Kong, J. L.; Marty, J. L.; Yu, C. Z.; Liu, B. H. Electrochemistry and biosensing activity of cytochrome c immobilized in macroporous materials. Microchim. Acta 2011, 175, 87–95.

    Article  Google Scholar 

  37. Guo, K.; Qian, K.; Zhang, S.; Kong, J. L.; Yu, C. Z.; Liu, B. H. Bio-electrocatalysis of NADH and ethanol based on graphene sheets modified electrodes. Talanta 2011, 85, 1174–1179.

    Article  Google Scholar 

  38. Zhang, S.; Hu, R.; Hu, P.; Wu, Z. S.; Shen, G. L.; Yu, R. Q. Blank peak current-suppressed electrochemical aptameric sensing platform for highly sensitive signal-on detection of small molecule. Nucleic Acids Res. 2010, 38, e185.

    Article  Google Scholar 

  39. Luo, J.; Ma, Q.; Wei, W.; Zhu, Y.; Liu, R.; Liu, X. Y.Synthesis of water-dispersible molecularly imprinted electroactive nanoparticles for the sensitive and selective paracetamol detection. ACS Appl. Mater. Interfaces 2016, 8, 21028–21038.

    Article  Google Scholar 

  40. Knezevic, J.; Langer, A.; Hampel, P. A.; Kaiser, W.; Strasser, R.; Rant, U. Quantitation of affinity, avidity, and binding kinetics of protein analytes with a dynamically switchable biosurface. J. Am. Chem. Soc. 2012, 134, 15225–15228.

    Article  Google Scholar 

  41. Rich, R. L.; Hoth, L. R.; Geoghegan, K. F.; Brown, T. A.; LeMotte, P. K.; Simons, S. P.; Hensley, P.; Myszka, D. G. Kinetic analysis of estrogen receptor/ligand interactions. Proc. Natl. Acad. Sci. USA 2002, 99, 8562–8567.

    Article  Google Scholar 

  42. Qian, K.; Zhou, L.; Liu, J.; Yang, J.; Xu, H. Y.; Yu, M. H.; Nouwens, A.; Zou, J.; Monteiro, M. J.; Yu, C. Z. Laser engineered graphene paper for mass spectrometry imaging. Sci. Rep. 2013, 3, 1415.

    Article  Google Scholar 

  43. Gan, J. R.; Wei, X.; Li, Y. X.; Wu, J.; Qian, K.; Liu, B. H. Designer SiO2@Au nanoshells towards sensitive and selective detection of small molecules in laser desorption ionization mass spectrometry. Nanomedicine NBM 2015, 11, 1715–1723.

    Article  Google Scholar 

  44. Liu, T. T.; Qu, L. L.; Qian, K.; Liu, J.; Zhang, Q.; Liu, L. H.; Liu, S. M. Raspberry-like hollow carbon nanospheres with enhanced matrix-free peptide detection profiles. Chem. Commun. 2016, 52, 1709–1712.

    Article  Google Scholar 

  45. Wei, X.; Liu, Z. H.; Jin, X. L.; Huang, L.; Gurav, D. D.; Sun, X. M.; Liu, B. H.; Ye, J.; Qian, K. Plasmonic nanoshells enhanced laser desorption/ionization mass spectrometry for detection of serum metabolites. Anal. Chim. Acta 2017, 950, 147–155.

    Article  Google Scholar 

  46. Wu, Y. J.; La Pierre, D. P.; Wu, J.; Yee, A. J.; Yang, B. B. The interaction of versican with its binding partners. Cell Res. 2005, 15, 483–494.

    Article  Google Scholar 

  47. Matsumoto, K.; Shionyu, M.; Go, M.; Shimizu, K.; Shinomura, T.; Kimata, K.; Watanabe, H. Distinct interaction of versican/PG-M with hyaluronan and link protein. J. Biol. Chem. 2003, 278, 41205–41212.

    Article  Google Scholar 

  48. Glatt, D. M.; Beckford Vera, D. R.; Parrott, M. C.; Luft, J. C.; Benhabbour, S. R.; Mumper, R. J. The interplay of antigen affinity, internalization, and pharmacokinetics on CD44-positive tumor targeting of monoclonal antibodies. Mol. Pharmaceutics 2016, 13, 1894–1903.

    Article  Google Scholar 

  49. Zhang, D.; Jia, H.; Wang, Y.; Li, W. M.; Hou, Y. C.; Yin, S. W.; Wang, T. D.; He, S. X.; Lu, S. Y. A CD44 specific peptide developed by phage display for targeting gastric cancer. Biotechnol. Lett. 2015, 37, 2311–2320.

    Article  Google Scholar 

  50. Lei, C.; Qian, K.; Noonan, O.; Nouwens, A.; Yu, C. Z. Applications of nanomaterials in mass spectrometry analysis. Nanoscale 2013, 5, 12033–12042.

    Article  Google Scholar 

  51. Li, Y. X.; Yan, L.; Liu, Y.; Qian, K.; Liu, B.; Yang, P. Y.; Liu, B. H. High-efficiency nano/micro-reactors for protein analysis. RSC Adv. 2015, 5, 1331–1342.

    Article  Google Scholar 

  52. Qian, K.; Wan, J. J.; Qiao, L.; Huang, X. D.; Tang, J. W.; Wang, Y. H.; Kong, J. L.; Yang, P. Y.; Yu, C. Z.; Liu, B. H. Macroporous materials as novel catalysts for efficient and controllable proteolysis. Anal. Chem. 2009, 81, 5749–5756.

    Article  Google Scholar 

  53. Gan, J. R.; Qian, K.; Wan, J. J.; Qiao, L.; Guo, W. C.; Yang, P. Y.; Girault, H. H.; Liu, B. H. Amino-functionalized macroporous silica for efficient tryptic digestion in acidic solutions. Proteomics 2013, 13, 3117–3123.

    Article  Google Scholar 

  54. Qian, K.; Zhou, L.; Zhang, J.; Lei, C.; Yu, C. Z. A combo-pore approach for the programmable extraction of peptides/proteins. Nanoscale 2014, 6, 5121–5125.

    Article  Google Scholar 

  55. Qian, K.; Liu, F.; Yang, J.; Huang, X. D.; Gu, W. Y.; Jambhrunkar, S.; Yuan, P.; Yu, C. Z. Pore size-optimized periodic mesoporous organosilicas for the enrichment of peptides and polymers. RSC Adv. 2013, 3, 14466–14472.

    Article  Google Scholar 

  56. Wan, J. J.; Qian, K.; Zhang, J.; Liu, F.; Wang, Y. H.; Yang, P. Y.; Liu, B. H.; Yu, C. Z. Functionalized periodic mesoporous organosilicas for enhanced and selective peptide enrichment. Langmuir 2010, 26, 7444–7450.

    Article  Google Scholar 

  57. Hu, Y. F.; Qian, K.; Yuan, P.; Wang, Y. H.; Yu, C. Z. Synthesis of large-pore periodic mesoporous organosilica. Mater. Lett. 2011, 65, 21–23.

    Article  Google Scholar 

  58. Qian, K.; Gu, W. Y.; Yuan, P.; Liu, F.; Wang, Y. H.; Monteiro, M.; Yu, C. Z. Enrichment and detection of peptides from biological systems using designed periodic mesoporous organosilica microspheres. Small 2012, 8, 231–236.

    Article  Google Scholar 

  59. Qian, K.; Wan, J. J.; Liu, F.; Girault, H. H.; Liu, B. H.; Yu, C. Z.A phospho-directed macroporous alumina-silica nanoreactor with multi-functions. ACS Nano 2009, 3, 3656–3662.

    Article  Google Scholar 

  60. Qian, K.; Wan, J. J.; Huang, X. D.; Yang, P. Y.; Liu, B. H.; Yu, C. Z. A smart glycol-directed nanodevice from rationally designed macroporous materials. Chem.—Eur. J. 2010, 16, 822–828.

    Article  Google Scholar 

  61. Wan, J. J.; Qian, K.; Qiao, L.; Wang, Y. H.; Kong, J. L.; Yang, P. Y.; Liu, B. H.; Yu, C. Z. TiO2-modified macroporous silica foams for advanced enrichment of multi-phosphorylated peptides. Chem.—Eur. J. 2009, 15, 2504–2508.

    Article  Google Scholar 

  62. Huang, L.; Wan, J.J.; Wei, X.; Liu, Y.; Huang, J. J.; Sun, X. M.; Zhang, R.; Gurav, D. D.; Vedarethinam, V.; Li, Y.; Chen, R. P.; Qian, K. Plasmonic silver nanoshells for drug and metabolite detection. Nat. Commun., in press, DOI: 10.1038/s41467-017-00220-4.

  63. Yang, Y. J.; Qi, Y.; Zhu, M.; Zhao, N. N.; Xu, F. J. Facile synthesis of wormlike quantum dots-encapsulated nanoparticles and their controlled surface functionalization for effective bioapplications. Nano Res. 2016, 9, 2531–2543.

    Article  Google Scholar 

  64. Liang, S.; Liu, Y.; Jin, X.; Liu, G.; Wen, J.; Zhang, L. L.; Li, J.; Yuan, X. B.; Chen, I. S. Y.; Chen, W.; Wang, H.; Shi, L. Q.; Zhu, X. Y.; Lu, Y. F. Phosphorylcholine polymer nanocapsules prolong the circulation time and reduce the immunogenicity of therapeutic proteins. Nano Res. 2016, 9, 1022–1031.

    Article  Google Scholar 

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Acknowledgements

We gratefully thank the financial support from National Natural Science Foundation of China (NSFC)(Nos. 81550110257 and 81401542), Shanghai Science and Technology Commission(No. 16441909300). This work is also sponsored by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No. TP2015015).

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  1. Chandrababu Rejeeth and Xuechao Pang contributed equally to this work.

Authors and Affiliations

  1. School of Biomedical Engineering, Shanghai Center for System Biomedicine, Shanghai Chest Hospital, and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China

    Chandrababu Rejeeth, Xuechao Pang, Ru Zhang, Wei Xu, Xuming Sun, Bin Liu, Jiatao Lou, Hongchen Gu, Wei Yan & Kun Qian

  2. Department of Chemistry, Shanghai University, Shanghai, 200444, China

    Jingjing Wan

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  1. Chandrababu Rejeeth
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  2. Xuechao Pang
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Correspondence to Wei Yan or Kun Qian.

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Rejeeth, C., Pang, X., Zhang, R. et al. Extraction, detection, and profiling of serum biomarkers using designed Fe3O4@SiO2@HA core–shell particles. Nano Res. 11, 68–79 (2018). https://doi.org/10.1007/s12274-017-1591-6

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