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Adsorption Induced Single Layer Area Increase and Collapse of Vesicles

Adsorption Induced Single Layer Area Increase and Collapse of Vesicles. Dan Hu Department of Mathematics &Institute of Natural Sciences Shanghai Jiao Tong University Joint work with Yukun Wang & Dongqing Wei. May 24,2012 @ Kavli Institute. Background---Antimicrobials.

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Adsorption Induced Single Layer Area Increase and Collapse of Vesicles

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  1. Adsorption Induced Single Layer Area Increase and Collapse of Vesicles Dan Hu Department of Mathematics &Institute of Natural Sciences Shanghai Jiao Tong University Joint work withYukun Wang & Dongqing Wei May 24,2012 @ Kavli Institute

  2. Background---Antimicrobials • Alarming increase in bacterial resistance • Traditional antibiotics --- drug resistance • Super bacteria • 2. Membrane - permeabilizing antimicrobial peptides (AMPs) • Less induced resistance • 3. Mimics of AMPs • Diversity • Possibly---Less metabolizable • Possibly---Low immunogenicity 

  3. AMP mechanisms Possible mechanism of membrane permeabilization induced by AMPs: William et al. 2011

  4. Mimics C8 (C6, C4) Polyoctamethylene guanidine hydrochloride is mimics of AMPs Amphiphilic & Charged C8 (n=3): 8 CH2 in each monomer.

  5. Leakage of fluorescence dye (50nm POPC liposome induced by C8)

  6. Leak mechanism of C8 • Charges Hard to form trans-membrane structures through thermal fluctuation • Maximum Leakage < 100% No steady trans-membrane pores • Possible mechanism Rupture of membrane? Instantaneous pores?

  7. Vesicle rupture Vesicles (POPC:PSM:CHOL=1:1:1) before and after applying C8 (50 )

  8. Effects of the drug Adsorption ---- out layer area increase ---- shape change & rupture

  9. Is the area really increased? ---- MD simulation Drug & POPC Effective area per lipid 0.685±0.008nm2 0.664±0.007nm2 0.638±0.009nm2 Pure POPC 0.615nm2 MD time (ns) C8 C6 C4

  10. Summary of area extension rate

  11. The molecular origin of different extension rate mammalian membrane by C4 and C8

  12. Experimental method • vesicle fluorescent dye leakage experiment • Dynamical light scatter experiment Used to measure the size distribution of the liposome in the solution The size and PDI (PolydisDersity Index) measured by dynamical light scatter With small PDI value With big PDI value

  13. Experimental validation on POPC membrane POPC vesicle fluorescent dye leakage experiment with different vesicle size 400nm The size and PDI (PolydisDersity Index) measured by dynamical light scatter 100nm 50nm

  14. Leakage result

  15. Modeling study Results: No rupture when is small. Small leakage when Multi-rupture

  16. Modeling study Other possible effects: 1. Partially filled Relaxation through deformation 2. Tolerance to stretch Energy barrier Effectively reduce

  17. Modeling study

  18. Add water C850ug/ml Drug effect POPC:PSM:CHOL =1:1:1 C650ug/ml C450ug/ml

  19. Experimental validation on mammalian membrane Add water C850ug/ml The size and PDI of liposome can be measured by Dynamic Light Scattering technique. C650ug/ml C450ug/ml

  20. conclusion 1. Area extension can induce vesicle rupture. 2.Content releasing and rupture are size dependent. 3. Differences in membranes can be used in drug designing.

  21. Thank you!

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