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Shear-stress sensitive lenticular vesicles for targeted drug delivery

Nature Nanotechnology volume 7, pages 536–543 (2012)Cite this article

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Abstract

Atherosclerosis results in the narrowing of arterial blood vessels and this causes significant changes in the endogenous shear stress between healthy and constricted arteries. Nanocontainers that can release drugs locally with such rheological changes can be very useful. Here, we show that vesicles made from an artificial 1,3-diaminophospholipid are stable under static conditions but release their contents at elevated shear stress. These vesicles have a lenticular morphology, which potentially leads to instabilities along their equator. Using a model cardiovascular system based on polymer tubes and an external pump to represent shear stress in healthy and constricted vessels of the heart, we show that drugs preferentially release from the vesicles in constricted vessels that have high shear stress.

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Figure 1: Chemical structures of phospholipids.
Figure 2: Confocal micrographs of GUVs and cryo-TEM micrographs of LUVET100s formulated from Pad–PC–Pad.
Figure 3: Release of carboxyfluorescein from vesicles made of phospholipids 1 to 5.
Figure 4: Monolayer studies of Pad–PC–Pad.
Figure 5: Release of entrapped fluorescent dye after passage through an extracorporeal pump flow set-up.
Figure 6: Fluorescence release patterns of EggPC vesicles with 10–100 mol% Pad–PC–Pad at 37 °C.

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Acknowledgements

This work was supported by the Swiss National Science Foundation via Research Program 62 ‘Smart Materials’ and the proof-of-principle fund of the University of Geneva. I.A.F., P.-L.Z. and A.Z. acknowledge support from the Swiss National Science Foundation (grant 200020_132035) and European Cooperation in Science and Technology Action D43. The authors thank the Electron Microscopy Center ETH Zurich and T. Ishikawa for cryo-TEM work, K. Peters for viability tests, and the Bioimaging, Mass Spectroscopy and Nuclear Magnetic Resonance facilities at the University of Geneva for analytical services, and the Critical Care Service at the University Hospitals of Geneva for the gift of the extracorporeal heart pump. The authors also appreciate scientific discussions with T. Fyles, A. Roux, F. Stellacci and T. Zemb.

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Authors and Affiliations

  1. Department of Organic Chemistry, University of Geneva, Quai Ernest-Ansermet 30, Geneva, 1211, Switzerland

    Margaret N. Holme, Illya A. Fedotenko, Daniel Abegg, Lucille Babel, France Favarger, Radu Tanasescu, Pierre-Léonard Zaffalon & Andreas Zumbuehl

  2. Biomaterials Science Center (BMC), University of Basel, c/o Universitätsspital, Basel, 4031, Switzerland

    Margaret N. Holme, Jasmin Althaus & Bert Müller

  3. Cardiology Division, Department of Medicine, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, 1211, Switzerland

    Margaret N. Holme & Till Saxer

  4. University of Freiburg, Experimental Polymer Physics, Hermann Herder Strasse 3, Freiburg, 79104, Germany

    Renate Reiter

  5. Biozentrum, University of Basel, Klingelbergstrasse 50/70, Basel, 4056, Switzerland

    André Ziegler

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  1. Margaret N. Holme
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Contributions

B.M., T.S. and A.Z. contributed the original idea, secured the financing and supervised the project. M.N.H., B.M., T.S. and A.Z. designed the experiments. I.A.F. synthesized Pad–PC–Pad. M.N.H., I.A.F., D.A., J.A., L.B., F.F., R.R., R.T., P-L.Z., A.Zi. and A.Z. performed the experiments. M.N.H., R.R., A.Zi., B.M., T.S. and A.Z. wrote the paper.

Corresponding authors

Correspondence to Bert Müller, Till Saxer or Andreas Zumbuehl.

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The authors declare no competing financial interests.

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Holme, M., Fedotenko, I., Abegg, D. et al. Shear-stress sensitive lenticular vesicles for targeted drug delivery. Nature Nanotech 7, 536–543 (2012). https://doi.org/10.1038/nnano.2012.84

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