Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery

Nature Nanotechnology volume 8, pages 763–771 (2013)Cite this article

Subjects

Abstract

Single-walled carbon nanotubes (SWNTs) can deliver imaging agents or drugs to tumours and offer significant advantages over approaches based on antibodies or other nanomaterials. In particular, the nanotubes can carry a substantial amount of cargo (100 times more than a monoclonal antibody), but can still be rapidly eliminated from the circulation by renal filtration, like a small molecule, due to their high aspect ratio. Here we show that SWNTs can target tumours in a two-step approach in which nanotubes modified with morpholino oligonucleotide sequences bind to cancer cells that have been pretargeted with antibodies modified with oligonucleotide strands complementary to those on the nanotubes. The nanotubes can carry fluorophores or radioisotopes, and are shown to selectively bind to cancer cells in vitro and in tumour-bearing xenografted mice. The binding process is also found to lead to antigen capping and internalization of the antibody–nanotube complexes. The nanotube conjugates were labelled with both alpha-particle and gamma-ray emitting isotopes, at high specific activities. Conjugates labelled with alpha-particle-generating 225Ac were found to clear rapidly, thus mitigating radioisotope toxicity, and were shown to be therapeutically effective in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Design and HPLC characterization of self-assembling SWNT–cMORF constructs
Figure 2: Self-assembly of SWNT–cMORF onto tumour cells pretargeted with mAb–MORF is highly specific and high in affinity.
Figure 3: SWNT–cMORF can selectively self-assemble onto pretargeted tumours in vivo.
Figure 4: SWNT–cMORF conjugates are able to induce antigen capping and internalization when self-assembled onto cells targeted with mAb–MORF (images organized in columns).
Figure 5: SWNT–cMORF–(225Ac)DOTA mitigates radioisotope toxicity and can be used as an effective agent in multistep therapy of disseminated lymphoma.
Figure 6: SWNT–cMORF–(225Ac)DOTA can be used as an effective agent in multistep therapy of disseminated lymphoma.

Similar content being viewed by others

References

  1. Scheinberg, D. A., Villa, C. H., Escorcia, F. E. & McDevitt, M. R. Conscripts of the infinite armada: systemic cancer therapy using nanomaterials. Nature Rev. Clin. Oncol. 7, 266–276 (2010).

    Article  CAS  Google Scholar 

  2. Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Rev. Drug Discov. 7, 771–782 (2008).

    Article  CAS  Google Scholar 

  3. Kostarelos, K., Bianco, A. & Prato, M. Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. Nature Nanotech. 4, 627–633 (2009).

    Article  CAS  Google Scholar 

  4. Liu, Z. et al. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res. 68, 6652–6660 (2008).

    Article  CAS  Google Scholar 

  5. Liu, Z. et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nature Nanotech. 2, 47–52 (2007).

    Article  CAS  Google Scholar 

  6. Villa, C. H. et al. Single-walled carbon nanotubes deliver peptide antigen into dendritic cells and enhance IgG responses to tumour-associated antigens. ACS Nano. 5, 5300–5311 (2011).

    Article  CAS  Google Scholar 

  7. Villa, C. H. et al. Synthesis and biodistribution of oligonucleotide-functionalized, tumour-targetable carbon nanotubes. Nano Lett. 8, 4221–4228 (2008).

    Article  CAS  Google Scholar 

  8. McDevitt, M. R. et al. PET imaging of soluble yttrium-86-labeled carbon nanotubes in mice. PLoS ONE 2, e907 (2007).

    Article  Google Scholar 

  9. McDevitt, M. R. et al. Tumour targeting with antibody-functionalized, radiolabeled carbon nanotubes. J. Nucl. Med. 48, 1180–1189 (2007).

    Article  CAS  Google Scholar 

  10. Ruggiero, A. et al. Imaging and treating tumour vasculature with targeted radiolabeled carbon nanotubes. Int. J. Nanomed. 5, 783–802 (2010).

    CAS  Google Scholar 

  11. Singh, R. et al. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc. Natl Acad. Sci. USA 103, 3357–3362 (2006).

    Article  CAS  Google Scholar 

  12. Liu, Z. et al. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc. Natl Acad. Sci. USA 105, 1410–1415 (2008).

    Article  CAS  Google Scholar 

  13. Mutlu, G. K. M. et al. Biocompatible nanoscale dispersion of single-walled carbon nanotubes minimizes in vivo pulmonary toxicity. Nano Lett. 10, 1664–1670 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Lacerda, L. et al. Carbon-nanotube shape and individualization critical for renal excretion. Small 4, 1130–1132 (2008).

    Article  CAS  Google Scholar 

  16. Kostarelos, K. Carbon nanotubes: fibrillar pharmacology. Nature Mater. 9, 793–795 (2010).

    Article  CAS  Google Scholar 

  17. Goldenberg, D., Sharkey, R., Paganelli, G. & Barbet, J. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J. Clin. Oncol. 10, 823–834 (2006).

    Article  Google Scholar 

  18. Green, D. J. et al. Pretargeted radioimmunotherapy for B-cell lymphomas. Clin. Cancer Res. 13, 5598s–5603s (2007).

    Article  CAS  Google Scholar 

  19. Sharkey, R. M. et al. Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody. Leukemia 19, 1064–1069 (2005).

    Article  CAS  Google Scholar 

  20. Liu, G. et al. Successful radiotherapy of tumour in pretargeted mice by 188Re-radiolabeled phosphorodiamidate morpholino oligomer, a synthetic DNA analogue. Clin. Cancer. Res. 12, 4958–4964 (2006).

    Article  CAS  Google Scholar 

  21. Rossin, R. et al. In vivo chemistry for pretargeted tumour imaging in live mice. Angew. Chem. Int. Ed. 49, 3375–3378 (2010).

    Article  CAS  Google Scholar 

  22. Park, J-H. et al. Cooperative nanomaterial system to sensitize, target, and treat tumours. Proc. Natl Acad. Sci. USA 107, 981–986 (2010).

    Article  CAS  Google Scholar 

  23. Perrault, S. D. & Chan, W. C. W. In vivo assembly of nanoparticle components to improve targeted cancer imaging. Proc. Natl Acad. Sci. USA 107, 11194–11199 (2010).

    Article  CAS  Google Scholar 

  24. Liu, G. et al. Adding a clearing agent to pretargeting does not lower the tumour accumulation of the effector as predicted. Cancer Biother. Radio. 25, 757–762 (2010).

    CAS  Google Scholar 

  25. Alvarez-Diez, T. M., Polihronis, J. & Reilly, R. M. Pretargeted tumour imaging with streptavidin immunoconjugates of monoclonal antibody CC49 and 111In-DTPA-biocytin. Nucl. Med. and Biol. 23, 459–466 (1996).

    Article  CAS  Google Scholar 

  26. He, J. et al. Affinity enhancement pretargeting: synthesis and testing of a (99m)Tc-labeled bivalent MORF. Mol. Pharmacol. 2, 1118–1124 (2010).

    Article  Google Scholar 

  27. Staii, C., Johnson, A. T., Chen, M. & Gelperin, A. DNA-decorated carbon nanotubes for chemical sensing. Nano Lett. 5, 1774–1778 (2005).

    Article  CAS  Google Scholar 

  28. Liu, G. et al. Tumour pretargeting in mice using (99m)Tc-labeled morpholino, a DNA analog. J. Nucl. Med. 43, 384–391 (2002).

    CAS  Google Scholar 

  29. Moulton, H. M. et al. Peptide–morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy. Ann. NY Acad. Sci. 1175, 55–60 (2009).

    Article  CAS  Google Scholar 

  30. Park, S. Y. et al. DNA-programmable nanoparticle crystallization. Nature 451, 553–556 (2008).

    Article  CAS  Google Scholar 

  31. Hnatowic, D. J. & Nakamura, K. The influence of chemical structure of DNA and other oligomer radiopharmaceuticals on tumour delivery. Curr. Opin. Mol. Ther. 8, 136–143 (2006).

    Google Scholar 

  32. Georgakilas, V. et al. Organic functionalization of carbon nanotubes. J. Am. Chem. Soc. 124, 760–761 (2002).

    Article  CAS  Google Scholar 

  33. Georgakilas, V. et al. Amino acid functionalisation of water soluble carbon nanotubes. Chem Commun. 3050–3051 (2002).

  34. McDevitt, M. R. et al. Tumour therapy with targeted atomic nanogenerators. Science 294, 1537–1540 (2001).

    Article  CAS  Google Scholar 

  35. He, J. et al. An improved method for covalently conjugating morpholino oligomers to antitumour antibodies. Bioconjug. Chem. 18, 983–988 (2007).

    Article  CAS  Google Scholar 

  36. Ackerman, M. E. et al. A33 antigen displays persistent surface expression. Cancer Immunol. Immunother. 57, 1017–1027 (2008).

    Article  CAS  Google Scholar 

  37. Welt, S. et al. Phase I study of anticolon cancer humanized antibody A33. Clin. Cancer Res. 9, 1338–1346 (2003).

    CAS  Google Scholar 

  38. Golay, J. et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 95, 3900–3908 (2000).

    CAS  Google Scholar 

  39. Miederer, M., Scheinberg, D. & McDevitt, M. Realizing the potential of the actinium-225 radionuclide generator in targeted alpha particle therapy applications. Adv. Drug Deliv. Rev. 60, 1371–1382 (2008).

    Article  CAS  Google Scholar 

  40. Song, H. et al. Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer Res. 69, 8941–8948 (2009).

    Article  CAS  Google Scholar 

  41. Miederer, M. et al. Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac–HuM195, in nonhuman primates. J. Nucl. Med. 45, 129–137 (2004).

    CAS  Google Scholar 

  42. Liu, G. & Hnatowich, D. J. A semiempirical model of tumour pretargeting. Bioconjug. Chem. 19, 2095–2104 (2008).

    Article  CAS  Google Scholar 

  43. Vegt, E. et al. Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J. Nucl. Med. 51, 1049–1058 (2010).

    Article  CAS  Google Scholar 

  44. Kaiser, E., Colescott, R. L., Bossinger, C. D. & Cook, P. I. Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal. Biochem. 34, 595–598 (1970).

    Article  CAS  Google Scholar 

  45. Liu, G. et al. Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice. Eur. J. Nucl. Med. Mol. I 34, 237–246 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the National Institutes of Health (NIH P01 CA33049 to D.A.S.; NIH R01 CA55349 to D.A.S.; R21 CA128406 to M.R.M.), the Office of Science (BER), the US Department of Energy (award no. DE-SC0002456 to M.R.M.), the NIH Medical Scientist Training Program (MSTP; grant GM07739 to J.J.M., C.H.V. and F.E.E.), the MSKCC Molecular Cytology Core Facility, the MSKCC Experimental Therapeutics Center, the MSKCC Brain Tumour Center and The Tudor and Glades Funds. The authors thank D. Hnatowich for helpful discussions. The authors also thank W. Maguire, S. Alidori and E. Feinberg for assistance, Actinium Pharmaceuticals for 225Ac acquisition, and M. Bergkvist for TEM and Raman spectroscopy.

Author information

Author notes

  1. J. Justin Mulvey and Carlos H. Villa: These authors contributed equally to this work

Authors and Affiliations

  1. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10065, USA

    J. Justin Mulvey, Carlos H. Villa, Freddy E. Escorcia, Emily Casey & David A. Scheinberg

  2. Weill-Cornell Medical College, 468 East 68th Street, New York, New York, 10065, USA

    J. Justin Mulvey, Carlos H. Villa, Freddy E. Escorcia & David A. Scheinberg

  3. Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10065, USA

    Michael R. McDevitt

  4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10065, USA

    Michael R. McDevitt & David A. Scheinberg

Authors
  1. J. Justin Mulvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos H. Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael R. McDevitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Freddy E. Escorcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emily Casey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David A. Scheinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.J.M., C.V., D.A.S. and M.M. conceived and designed the experiments and wrote the paper. C.V. and J.J.M. conducted all the experiments. E.C. assisted with confocal microscopy experiments. F.E. assisted with solid tumour targeting experiments.

Corresponding author

Correspondence to David A. Scheinberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Information (PDF 9490 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mulvey, J., Villa, C., McDevitt, M. et al. Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery. Nature Nanotech 8, 763–771 (2013). https://doi.org/10.1038/nnano.2013.190

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2013.190

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing