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Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface

Nature Nanotechnology volume 8, pages 137–143 (2013)Cite this article

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Abstract

Nanoparticles have been proposed as carriers for drugs, genes and therapies to treat various diseases1,2. Many strategies have been developed to target nanomaterials to specific or over-expressed receptors in diseased cells, and these typically involve functionalizing the surface of nanoparticles with proteins, antibodies or other biomolecules. Here, we show that the targeting ability of such functionalized nanoparticles may disappear when they are placed in a biological environment. Using transferrin-conjugated nanoparticles, we found that proteins in the media can shield transferrin from binding to both its targeted receptors on cells and soluble transferrin receptors. Although nanoparticles continue to enter cells, the targeting specificity of transferrin is lost. Our results suggest that when nanoparticles are placed in a complex biological environment, interaction with other proteins in the medium and the formation of a protein corona3,4 can ‘screen’ the targeting molecules on the surface of nanoparticles and cause loss of specificity in targeting.

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Figure 1: Nanoparticle synthesis scheme.
Figure 2: Interaction of functional PEGylated human Tf particles (SiO2–PEG8–Tf) with soluble TfR and uptake in A549 cells.
Figure 3: Interaction of surface-grafted human Tf particles (SiO2–Tf), PEGylated and PEGylated bovine Tf particles (SiO2–PEG8 and SiO2–PEG8–bTf) with soluble TfR and A549 cells.
Figure 4: In situ targeting of SiO2–PEG8–Tf nanoparticles with soluble TfR, and uptake in A549 in the presence of serum.

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References

  1. Ruoslahti, E., Bhatia, S. N. & Sailor, M. J. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188, 759–768 (2010).

    Article  CAS  Google Scholar 

  2. Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nature Rev. Cancer 5, 161–171 (2005).

    Article  CAS  Google Scholar 

  3. Cedervall, T. et al. Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc. Natl Acad. Sci. USA 104, 2050–2055 (2007).

    Article  CAS  Google Scholar 

  4. Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nature Mater. 8, 543–557 (2009).

    Article  CAS  Google Scholar 

  5. Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4, 128–139 (2012).

    Article  Google Scholar 

  6. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).

    Article  CAS  Google Scholar 

  7. Keystone, E. et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 58, 3319–3329 (2008).

    Article  CAS  Google Scholar 

  8. Ferrari, M. Frontiers in cancer nanomedicine: directing mass transport through biological barriers. Trends Biotechnol. 28, 181–188 (2010).

    Article  CAS  Google Scholar 

  9. Nie, S., Xing, Y., Kim, G. J. & Simons, J. W. Nanotechnology applications in cancer. Annu. Rev. Biomed. Eng. 9, 257–288 (2007).

    Article  CAS  Google Scholar 

  10. Zamboni, W. C. et al. Best practices in cancer nanotechnology: perspective from NCI Nanotechnology Alliance. Clin. Cancer Res. 18, 3229–3241 (2012).

    Article  CAS  Google Scholar 

  11. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nature Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  Google Scholar 

  12. Moghimi, S. M., Hunter, A. C. & Murray, J. C. Nanomedicine: current status and future prospects. FASEB J. 19, 311–330 (2005).

    Article  CAS  Google Scholar 

  13. Salvati, A. et al. Experimental and theoretical comparison of intracellular import of polymeric nanoparticles and small molecules: toward models of uptake kinetics. Nanomedicine NBM 7, 818–826 (2011).

    Article  CAS  Google Scholar 

  14. Iversen, T-G., Skotland, T. & Sandvig, K. Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies. Nano Today 6, 176–185 (2011).

    Article  CAS  Google Scholar 

  15. Mitragotri, S. & Lahann, J. Physical approaches to biomaterial design. Nature Mater. 8, 15–23 (2009).

    Article  CAS  Google Scholar 

  16. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nature Rev. Drug Discov. 9, 615–627 (2010).

    Article  CAS  Google Scholar 

  17. Decuzzi, P. et al. Size and shape effects in the biodistribution of intravascularly injected particles. J. Control. Rel. 141, 320–327 (2010).

    Article  CAS  Google Scholar 

  18. Barenholz, Y. Liposome application: problems and prospects. Curr. Opin. Colloid Interface Sci. 6, 66–77 (2001).

    Article  CAS  Google Scholar 

  19. Farma, J. M. et al. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor. Int. J. Cancer 120, 2474–2480 (2007).

    Article  CAS  Google Scholar 

  20. Paciotti, G. F. et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Del. 11, 169–183 (2004).

    Article  CAS  Google Scholar 

  21. Deng, Z. J. et al. Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nature Nanotech. 6, 39–44 (2011).

    Article  CAS  Google Scholar 

  22. Wang, J. et al. Soft interactions at nanoparticles alter protein function and conformation in a size dependent manner. Nano Lett. 11, 4985–4991 (2011).

    Article  CAS  Google Scholar 

  23. Otsuka, H., Nagasaki, Y. & Kataoka, K. PEGylated nanoparticles for biological and pharmaceutical applications. Adv. Drug Del. Rev. 55, 403–419 (2003).

    Article  CAS  Google Scholar 

  24. Hamad, I. et al. Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering. ACS Nano 4, 6629–6638 (2010).

    Article  CAS  Google Scholar 

  25. Daniels, T. R., Delgado, T., Helguera, G. & Penichet, M. L. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin. Immunol. 121, 159–176 (2006).

    Article  CAS  Google Scholar 

  26. Thorstensen, K. & Romslo, I. The role of transferrin in the mechanism of cellular iron uptake. Biochem. J. 271, 1–10 (1990).

    Article  CAS  Google Scholar 

  27. Kumar, R. et al. Covalently dye-linked, surface-controlled, and bioconjugated organically modified silica nanoparticles as targeted probes for optical imaging. ACS Nano 2, 449–456 (2008).

    Article  CAS  Google Scholar 

  28. Högemann-Savellano, D. et al. The transferrin receptor: a potential molecular imaging marker for human cancer. Neoplasia 5, 495–506 (2003).

    Article  Google Scholar 

  29. Qian, J. et al. Bio-molecule-conjugated fluorescent organically modified silica nanoparticles as optical probes for cancer cell imaging. Opt. Express 16, 19568–19578 (2008).

    Article  CAS  Google Scholar 

  30. Wu, J., Ye, Z., Wang, G. & Yuan, J. Multifunctional nanoparticles possessing magnetic, long-lived fluorescence and bio-affinity properties for time-resolved fluorescence cell imaging. Talanta 72, 1693–1697 (2007).

    Article  CAS  Google Scholar 

  31. Kim, J. A., Åberg, C., Salvati, A. & Dawson, K. A. Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. Nature Nanotech. 7, 62–68 (2012).

    Article  CAS  Google Scholar 

  32. Shibuya-Fujiwara, N. et al. Phagocytosis in vitro of polyethylene glycol-modified liposome-encapsulated hemoglobin by human peripheral blood monocytes plus macrophages through scavenger receptors. Life Sci. 70, 291–300 (2001).

    Article  CAS  Google Scholar 

  33. Walczyk, D. et al. What the cell ‘sees' in bionanoscience. J. Am. Chem. Soc. 132, 5761–5768 (2010).

    Article  CAS  Google Scholar 

  34. Chakravarty, P. et al. Thermal ablation of tumor cells with antibody-functionalized single-walled carbon nanotubes. Proc. Natl Acad. Sci. USA 105, 8697–8702 (2008).

    Article  CAS  Google Scholar 

  35. Hirsch, L. R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl Acad. Sci. USA 100, 13549–13554 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding for this project was provided by the INSPIRE (Integrated NanoScience Platform for Ireland) programme (funded by the Irish Government's Programme for Research in Third Level Institutions, Cycle 4, National Development Plan 2007-2013), the Irish Research Council for Science, Engineering and Technology, the Helmholtz-Gemeinschaft Deutscher Forschungszentren e. V. Virtual Institute grant Nano Tracking (agreement no. VH-VI-421) and Science Foundation Ireland (09/RFP/MTR2425). This work was based on work supported by the Small Collaborative projects NeuroNano (NNP4-SL-2008-214547) and NanoTransKinetics (NMP4-2010-EU-US-266737), as well as the projects 3micron (NMP-2009-LARGE-3-246479) and NAMDIATREAM (NMP4-LA-2010-246479), funded by the European Commission 7th Framework Programme. The ESF Research Networking Programme EpitopeMap is also acknowledged, as well as use of the Conway Institute Flow Cytometry and Imaging Facilities and the Biological Imaging Suite at University College Dublin. J.C. Simpson is thanked for assistance with RNA interference experiments.

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Authors and Affiliations

  1. Centre for BioNano Interactions, School of Chemistry and Chemical Biology, UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, 4, Dublin, Ireland

    Anna Salvati, Andrzej S. Pitek, Marco P. Monopoli, Kanlaya Prapainop, Francesca Baldelli Bombelli, Delyan R. Hristov, Philip M. Kelly, Christoffer Åberg, Eugene Mahon & Kenneth A. Dawson

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  1. Anna Salvati
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Contributions

A.S. performed experiments on cells, analysed and interpreted the data, and wrote the paper. A.S.P. performed biological interaction experiments, analysed and interpreted the data, and contributed to writing the paper. E.M. performed synthesis and characterization of nanoparticles, analysed and interpreted the data, and wrote the paper. M.P.M. prepared and characterized the depleted serum, analysed and interpreted the data, and contributed to writing the paper. K.P. contributed to silencing and competition experiments. D.R.H. and P.M.K. contributed to the synthesis and characterization of the particles, respectively. F.B.B. and C.Å. analysed and interpreted the data and contributed to writing the paper. K.A.D. conceived and designed the experiments, analysed and interpreted the data, and wrote the paper.

Corresponding authors

Correspondence to Eugene Mahon or Kenneth A. Dawson.

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Salvati, A., Pitek, A., Monopoli, M. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nature Nanotech 8, 137–143 (2013). https://doi.org/10.1038/nnano.2012.237

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