Liposome transduction into cells enhanced by haptotactic peptides (Haptides) homologous to fibrinogen C-termini

Raphael Gorodetsky*, Lila Levdansky, Akiva Vexler, Irina Shimeliovich, Ibrahim Kassis, Matti Ben-Moshe, Shlomo Magdassi, Gerard Marx

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Haptides are 19-21mer cell-binding peptides equivalent to sequences on the C-termini of fibrinogen β chain (Cβ), γ chain (preCγ) and the extended αE chain of fibrinogen (CαE). In solution, Haptides accumulated in cells by non-saturable kinetics [Exp. Cell Res. 287 (2003) 116]. This study describes Haptide interactions with liposomes and Haptide-mediated liposome uptake by cells. Haptides became incorporated into negatively charged liposomes, changing their zeta potential. Atomic force microscopy and particle sizing by light scattering showed that the liposomes dissolved Haptide nanoparticles and absorbed them from solution. Pre-mixing fluorescent rhodamine-containing liposomes or "stealth" doxorubicin (DOX)-containing liposomes (Doxil) with Cβ, preCγ or to a lesser degree CαE, significantly enhanced their uptake by fibroblasts and endothelial cells. Confocal microscopy showed Haptide-induced liposome uptake saturated above ∼40 μM Haptide. Cytotoxicity tests with lower concentrations of Doxil liposomes indicated that premixing with ∼40 μM Cβ or preCγ increased their toxicity by one order of magnitude. It was evident that the liposomes complexed with an amphiphilic Haptide are transduced through cell membranes, probably by a non-receptor-mediated process. These results suggest that Cβ or pre-Cγ could be employed to augment the cellular uptake of drugs in liposomal formulations.

Original languageAmerican English
Pages (from-to)477-488
Number of pages12
JournalJournal of Controlled Release
Volume95
Issue number3
DOIs
StatePublished - 24 Mar 2004

Bibliographical note

Funding Information:
We thank Dr. Alexander Tabachnick and Prof. Alberto Gabizon for supplying some of the drugs and helpful advises. We also wish to thank Dr. Mark Tarshish for his help in confocal microscopy and Dr. Anna Hotovely-Solomon for some technical help. This work was partially supported by the Israel Science Foundation Grant #697/001 to R.G. and by HAPTO Biotech.

Keywords

  • Cell-membrane
  • DOX
  • Doxil
  • Doxorubicin
  • Doxorubicin-loaded stealth (PEG-coated) liposomes
  • FITC
  • Fibrin and/or fibrinogen
  • Fibrin(ogen)
  • Fibrinopeptides
  • Fluorescein isothiocyanate
  • Haptides
  • Liposomes
  • Rhodamine
  • Transduction

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