Article

Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy

  • Nature Biomedical Engineeringvolume 2pages95103 (2018)
  • doi:10.1038/s41551-017-0187-5
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Abstract

Bacterial resistance to antibiotics has made it necessary to resort to using antibacterial drugs that have considerable toxicities. Here, we show that conjugation of vancomycin-loaded nanoparticles with the cyclic 9-amino-acid peptide CARGGLKSC (CARG), identified via phage display on Staphylococcus aureus (S. aureus) bacteria and through in vivo screening in mice with S. aureus-induced lung infections, increases the antibacterial activity of the nanoparticles in S. aureus-infected tissues and reduces the systemic dose needed, minimizing side effects. CARG binds specifically to S. aureus bacteria but not Pseudomonas bacteria in vitro, selectively accumulates in S. aureus-infected lungs and skin of mice but not in non-infected tissue and Pseudomonas-infected tissue, and significantly enhances the accumulation of intravenously injected vancomycin-loaded porous silicon nanoparticles bearing CARG in S. aureus-infected mouse lung tissue. The targeted nanoparticles more effectively suppress staphylococcal infections in vivo relative to equivalent doses of untargeted vancomycin nanoparticles or of free vancomycin. The therapeutic delivery of antibiotic-carrying nanoparticles bearing peptides targeting infected tissues may help combat difficult-to-treat infections.

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Acknowledgements

We thank V. R. Kotamraju for peptide synthesis and J. Ward for technical assistance. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement HR0011-13-2-0017, the National Science Foundation grant no. CBET-1603177 and in part by the National Institutes of Health, through contract no. R01 AI132413-01. The content of the information within this document does not necessarily reflect the position or the policy of the Government. This research was also supported in part by a grant from the Basic Science Research Program through the Korea NRF funded by the Ministry of Education (grant no. 2017R1D1A1B03035525), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Korea (grant no. HI14C1090), and by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012).

Author information

Author notes

    • Gary B. Braun

    Present address: STEMCELL Technologies Inc., Vancouver, Canada

    • Zhi-Gang She

    Present address: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

  1. Sazid Hussain and Jinmyoung Joo contributed equally to this work.

Affiliations

  1. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    • Sazid Hussain
    • , Gary B. Braun
    • , Zhi-Gang She
    • , Aman P. Mann
    • , Tambet Teesalu
    •  & Erkki Ruoslahti
  2. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA

    • Jinmyoung Joo
    • , Dokyoung Kim
    •  & Michael J. Sailor
  3. Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea

    • Jinmyoung Joo
  4. Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea

    • Jinmyoung Joo
  5. Department of Nanoengineering, University of California, San Diego, La Jolla, CA, USA

    • Jinyoung Kang
    •  & Michael J. Sailor
  6. Materials Science and Engineering Program, University of California, San Diego, La Jolla, CA, USA

    • Byungji Kim
    •  & Michael J. Sailor
  7. Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

    • Tarmo Mölder
    •  & Tambet Teesalu
  8. Center for Nanomedicine, and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA

    • Tambet Teesalu
    •  & Erkki Ruoslahti
  9. Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali- ChiBioFarAm, Università di Messina, Messina, Italy

    • Santina Carnazza
    •  & Salvatore Guglielmino

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Contributions

S.H. performed phage display screening and validated the Staphylococcus-binding peptide. J.J., G.B.B. and D.K. designed, synthesized and characterized nanoparticles, performed in vitro experiments. S.H., J.J., G.B.B., Z.-G.S., J.K. and B.K. performed and analysed in vivo experiments. S.H., A.P.M., T.M. and T.T. performed Ion Torrent data analysis. S.C. and S.G. identified the Pseudomonas-binding peptide. S.H., J.J., G.B.B., D.K., B.K., J.K., M.J.S. and E.R. discussed and analysed data. S.H., J.J., M.J.S. and E.R. conceived the project, and wrote the manuscript. All authors read and approved the manuscript.

Competing interests

M.J.S. is a scientific founder of Spinnaker Biosciences, Inc., and has an equity interest in the company. Although the R01 AI132413-01 grant has been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Spinnaker Biosciences, Inc., the research findings included in this particular publication may not necessarily relate to the interests of Spinnaker Biosciences, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. All the other authors declare no competing financial interests.

Corresponding author

Correspondence to Erkki Ruoslahti.

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