Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles

Sergey G. Tarasov, Vadim Gaponenko, O. M Zack Howard, Yuhong Chen, Joost J. Oppenheim, Marzena A. Dyba, Sriram Subramaniam, Youngshim Lee, Christopher Michejda, Nadya I. Tarasova

Research output: Contribution to journalArticle

Abstract

Significant efforts have been devoted to the development of nanoparticular delivering systems targeting tumors. However, clinical application of nanoparticles is hampered by insufficient size homogeneity, difficulties in reproducible synthesis and manufacturing, frequent high uptake in the liver, systemic toxicity of the carriers (particularly for inorganic nanoparticles), and insufficient selectivity for tumor cells. We have found that properly modified synthetic analogs of transmembrane domains of membrane proteins can self-assemble into remarkably uniform spherical nanoparticles with innate biological activity. Self-assembly is driven by a structural transition of the peptide that adopts predominantly a beta-hairpin conformation in aqueous solutions, but folds into an alpha-helix upon spontaneous fusion of the nanoparticles with cell membrane. A 24-amino acid peptide corresponding to the second transmembrane helix of the CXCR4 forms self-assembled particles that inhibit CXCR4 function in vitro and hamper CXCR4-dependent tumor metastasis in vivo. Furthermore, such nanoparticles can encapsulate hydrophobic drugs, thus providing a delivery system with the potential for dual biological activity.

Original languageEnglish (US)
Pages (from-to)9798-9803
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number24
DOIs
StatePublished - Jun 14 2011
Externally publishedYes

Keywords

  • Cancer
  • CXCL12
  • Undruggable target
  • Virus-like particles

ASJC Scopus subject areas

  • General

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  • Cite this

    Tarasov, S. G., Gaponenko, V., Howard, O. M. Z., Chen, Y., Oppenheim, J. J., Dyba, M. A., Subramaniam, S., Lee, Y., Michejda, C., & Tarasova, N. I. (2011). Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles. Proceedings of the National Academy of Sciences of the United States of America, 108(24), 9798-9803. https://doi.org/10.1073/pnas.1014598108