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Thermodynamics of Lipid Interactions with Cell-Penetrating Peptides

  • Reto Sauder
  • Joachim Seelig
  • André Ziegler
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 683)

Abstract

Cationic peptides are efficiently taken up by biological cells through different pathways, which can be exploited for delivery of intracellular drugs. For example, their endocytosis is known since 1967, and this typically produces entrapment of the peptides in endocytotic vesicles. The resulting peptide (and cargo) degradation in lysosomes is of little therapeutic interest. Beside endocytosis (and various subtypes thereof), cationic cell-penetrating peptides (CPPs) may also gain access to cytosol and nucleus of livings cells. This process is known since 1988, but it is poorly understood whether the cytosolic CPP appearance requires an active cellular machinery with membrane proteins and signaling molecules, or whether this translocation occurs by passive diffusion and thus can be mimicked with model membranes devoid of proteins or glycans. In the present chapter, protocols are presented that allow for testing the membrane binding and disturbance of CPPs on model membranes with special focus on particular CPP properties. Protocols include vesicle preparation, lipid quantification, and analysis of membrane leakage, lipid polymorphism (31P NMR), and membrane binding (isothermal titration calorimetry). Using these protocols, a major difference among CPPs is observed: At low micromolar concentration, nonamphipathic CPPs, such as nona-arginine (WR9) and penetratin, have only a poor affinity for model membranes with a lipid composition typical of eukaryotic membranes. No membrane leakage is induced by these compounds at low micromolar concentration. In contrast, their amphipathic derivatives, such as acylated WR9 (C14, C16, C18) or amphipathic penetratin mutant p2AL (Drin et al., Biochemistry 40:1824–1834, 2001), bind and disturb lipid model membranes already at low micromolar peptide concentration. This suggests that the mechanism for cytosolic CPP delivery (and potential toxicity) differs among CPPs despite their common name.

Key words

Cell membrane Drug delivery Liposomes Membrane anchor Protein transport 

Notes

Acknowledgments

This work was supported by the Swiss National Science Founda tion (SNF) Grant # 31.107793.

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Copyright information

© Springer Sciecne+Business Media, LLC 2011

Authors and Affiliations

  • Reto Sauder
    • 1
  • Joachim Seelig
    • 2
  • André Ziegler
    • 2
  1. 1.Department of Biophysical ChemistryBiozentrum of the University of BaselBaselSwitzerland
  2. 2.Department of Biophysical ChemistryBiozentrum of the University of BaselBaselSwitzerland

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