Encapsulated Multi-vesicle Assemblies of Programmable Architecture: Towards Personalized Healthcare

  • Maik Hadorn
  • Peter Eggenberger Hotz
Part of the Communications in Computer and Information Science book series (CCIS, volume 127)


Although single artificial vesicles are successfully used as delivery vehicles of pharmaceuticals, unilamellarity and restriction to one vessel result in premature content release in physiological environments as well as problems in simultaneous entrapment of a given set of (pharmaceutical) components. Multilamellarity and assemblies of distinct populations of vesicles are proposed to solve these problems. In this study, we provide a novel encapsulation protocol to fabricate multilamellar vesicles and we report on the DNA-mediated self-assembly of more than two distinct populations of vesicles. We discuss how these results might be used in personalized healthcare based on custom-tailored encapsulated multicompartment vesicular drug delivery systems.


Personalized healthcare Drug delivery Encapsulation Compartmentalization Programmability Vesicle Liposome 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bedau, M.A., McCaskill, J.S., Packard, N.H., Rasmussen, S.: Living Technology: Exploiting Life’s Principles in Technology. Artif. Life 16, 89–97 (2009)CrossRefGoogle Scholar
  2. 2.
    Chan, Y.H.M., van Lengerich, B., Boxer, S.G.: Effects of linker sequences on vesicle fusion mediated by lipid-anchored DNA oligonucleotides. Proc. Natl. Acad. Sci. USA 106, 979–984 (2009)CrossRefGoogle Scholar
  3. 3.
    Hase, M., Yoshikawa, K.: Structural transition of actin filament in a cell-sized water droplet with a phospholipid membrane. J. Chem. Phys. 124, 104903 (2006)CrossRefGoogle Scholar
  4. 4.
    Hotani, H., Nomura, F., Suzuki, Y.: Giant liposomes: from membrane dynamics to cell morphogenesis. Curr. Opin. Colloid Interface Sci. 4, 358–368 (1999)CrossRefGoogle Scholar
  5. 5.
    Limozin, L., Roth, A., Sackmann, E.: Microviscoelastic moduli of biomimetic cell envelopes. Phys. Rev. Lett. 95, 178101 (2005)CrossRefGoogle Scholar
  6. 6.
    Luisi, P., Walde, P.: Giant vesicles. John Wiley & Sons, Ltd, Chichester (2000)Google Scholar
  7. 7.
    Gomez-Hens, A., Fernandez-Romero, J.M.: The role of liposomes in analytical processes. Trac-Trends Anal. Chem. 24, 9–19 (2005)CrossRefGoogle Scholar
  8. 8.
    Owen, R.L., Strasters, J.K., Breyer, E.D.: Lipid vesicles in capillary electrophoretic techniques: Characterization of structural properties and associated membrane-molecule interactions. Electrophoresis 26, 735–751 (2005)CrossRefGoogle Scholar
  9. 9.
    Wiedmer, S.K., Jussila, M.S., Riekkola, M.L.: Phospholipids and liposomes in liquid chromatographic and capillary electromigration techniques. Trac-Trends Anal. Chem. 23, 562–582 (2004)CrossRefGoogle Scholar
  10. 10.
    Jesorka, A., Orwar, O.: Liposomes: Technologies and Analytical Applications. Annu. Rev. Anal. Chem. 1, 801–832 (2008)CrossRefGoogle Scholar
  11. 11.
    Michel, M., Winterhalter, M., Darbois, L., Hemmerle, J., Voegel, J.C., Schaaf, P., Ball, V.: Giant liposome microreactors for controlled production of calcium phosphate crystals. Langmuir 20, 6127–6133 (2004)CrossRefGoogle Scholar
  12. 12.
    Noireaux, V., Libchaber, A.: A vesicle bioreactor as a step toward an artificial cell assembly. Proc. Natl. Acad. Sci. USA 101, 17669–17674 (2004)CrossRefGoogle Scholar
  13. 13.
    Nomura, S., Tsumoto, K., Hamada, T., Akiyoshi, K., Nakatani, Y., Yoshikawa, K.: Gene expression within cell-sized lipid vesicles. Chembiochem. 4, 1172–1175 (2003)CrossRefGoogle Scholar
  14. 14.
    Bolinger, P.Y., Stamou, D., Vogel, H.: Integrated nanoreactor systems: Triggering the release and mixing of compounds inside single vesicles. J. Am. Chem. Soc. 126, 8594–8595 (2004)CrossRefGoogle Scholar
  15. 15.
    Bolinger, P.Y., Stamou, D., Vogel, H.: An integrated self-assembled nanofluidic system for controlled biological chemistries. Angew. Chem.-Int. Edit. 47, 5544–5549 (2008)CrossRefGoogle Scholar
  16. 16.
    Chiu, D.T., Wilson, C.F., Ryttsen, F., Stromberg, A., Farre, C., Karlsson, A., Nordholm, S., Gaggar, A., Modi, B.P., Moscho, A., Garza-Lopez, R.A., Orwar, O., Zare, R.N.: Chemical transformations in individual ultrasmall biomimetic containers. Science 283, 1892–1895 (1999)CrossRefGoogle Scholar
  17. 17.
    Kuruma, Y., Stano, P., Ueda, T., Luisi, P.L.: A synthetic biology approach to the construction of membrane proteins in semi-synthetic minimal cells. Biochim. Biophys. Acta-Biomembr. 1788, 567–574 (2009)CrossRefGoogle Scholar
  18. 18.
    Kita, H., Matsuura, T., Sunami, T., Hosoda, K., Ichihashi, N., Tsukada, K., Urabe, I., Yomo, T.: Replication of Genetic Information with Self-Encoded Replicase in Liposomes. Chembiochem. 9, 2403–2410 (2008)CrossRefGoogle Scholar
  19. 19.
    Chiarabelli, C., Stano, P., Luisi, P.L.: Chemical approaches to synthetic biology. Curr. Opin. Biotechnol. 20, 492–497 (2009)CrossRefGoogle Scholar
  20. 20.
    Abraham, S.A., Waterhouse, D.N., Mayer, L.D., Cullis, P.R., Madden, T.D., Bally, M.B.: The liposomal formulation of doxorubicin. In: Liposomes. Pt E. Elsevier Academic Press Inc., San Diego (2005)Google Scholar
  21. 21.
    Allen, T.M.: Liposomal drug delivery. Curr. Opin. Colloid Interface Sci. 1, 645–651 (1996)CrossRefGoogle Scholar
  22. 22.
    Allen, T.M., Cullis, P.R.: Drug delivery systems: Entering the mainstream. Science 303, 1818–1822 (2004)CrossRefGoogle Scholar
  23. 23.
    Allen, T.M., Hansen, C., Martin, F., Redemann, C., Yauyoung, A.: Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochimica Et Biophysica Acta 1066, 29–36 (1991)CrossRefGoogle Scholar
  24. 24.
    Allen, T.M., Hansen, C.B., Demenezes, D.E.L.: Pharmacokinetics of long-circulating liposomes. Adv. Drug Deliv. Rev. 16, 267–284 (1995)CrossRefGoogle Scholar
  25. 25.
    Boutorin, A.S., Guskova, L.V., Ivanova, E.M., Kobetz, N.D., Zarytova, V.F., Ryte, A.S., Yurchenko, L.V., Vlassov, V.V.: Synthesis of alkylating oligonucleotide derivatives containing cholesterol or phenazinium residues at their 3’-terminus and their interaction with DNA within mammalian-cells. FEBS Lett. 254, 129–132 (1989)CrossRefGoogle Scholar
  26. 26.
    Marjan, J.M.J., Allen, T.M.: Long circulating liposomes: Past, present and future. Biotechnology Advances 14, 151–175 (1996)CrossRefGoogle Scholar
  27. 27.
    Tardi, P.G., Boman, N.L., Cullis, P.R.: Liposomal doxorubicin. J. Drug Target. 4, 129–140 (1996)CrossRefGoogle Scholar
  28. 28.
    Sengupta, S., Eavarone, D., Capila, I., Zhao, G.L., Watson, N., Kiziltepe, T., Sasisekharan, R.: Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005)CrossRefGoogle Scholar
  29. 29.
    Hadorn, M., Eggenberger Hotz, P.: Towards Personalized Drug Delivery: Preparation of an Encapsulated Multicompartment System. In: 3rd International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC), Valencia, Spain (in press, 2010)Google Scholar
  30. 30.
    Kisak, E., Coldren, B., Evans, C., Boyer, C., Zasadzinski, J.: The vesosome - A multicompartment drug delivery vehicle. Current medicinal chemistry 11, 199–220 (2004)CrossRefGoogle Scholar
  31. 31.
    Torchilin, V.P.: Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4, 145–160 (2005)CrossRefGoogle Scholar
  32. 32.
    Bonacucina, G., Cespi, M., Misici-Falzi, M., Palmieri, G.F.: Colloidal Soft Matter as Drug Delivery System. J. Pharm. Sci. 98, 1–42 (2009)CrossRefGoogle Scholar
  33. 33.
    Theodossiou, T.A., Galanou, M.C., Paleos, C.M.: Novel amiodarone-doxorubicin cocktail liposomes enhance doxorubicin retention and cytotoxicity in DU145 human prostate carcinoma cells. J. Med. Chem. 51, 6067–6074 (2008)CrossRefGoogle Scholar
  34. 34.
    Lasic, D., Vallner, J., Working, P.: Sterically stabilized liposomes in cancer therapy and gene delivery. Current opinion in molecular therapeutics 1, 177–185 (1999)Google Scholar
  35. 35.
    Eckstein, F.: The versatility of oligonucleotides as potential therapeutics. Expert Opin. Biol. Ther. 7, 1021–1034 (2007)CrossRefGoogle Scholar
  36. 36.
    Weissig, V., Boddapati, S., Cheng, S., D’souza, G.: Liposomes and liposome-like vesicles for drug and DNA delivery to mitochondria. Journal of Liposome Research 16, 249–264 (2006)CrossRefGoogle Scholar
  37. 37.
    Bakker-Woudenberg, I., Schiffelers, R.M., Storm, G., Becker, M.J., Guo, L.: Long-circulating sterically stabilized liposomes in the treatment of infections. In: Liposomes. Pt E. Elsevier Academic Press Inc., San Diego (2005)Google Scholar
  38. 38.
    Torchilin, V.: Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur. J. Pharm. Biopharm. 71, 431–444 (2009)CrossRefGoogle Scholar
  39. 39.
    Boyer, C., Zasadzinski, J.A.: Multiple lipid compartments slow vesicle contents release in lipases and serum. ACS Nano 1, 176–182 (2007)CrossRefGoogle Scholar
  40. 40.
    Luisi, P.L., de Souza, T.P., Stano, P.: Vesicle Behavior: In Search of Explanations. J. Phys. Chem. B 112, 14655–14664 (2008)CrossRefGoogle Scholar
  41. 41.
    Walker, S.A., Kennedy, M.T., Zasadzinski, J.A.: Encapsulation of bilayer vesicles by self-assembly. Nature 387, 61–64 (1997)CrossRefGoogle Scholar
  42. 42.
    Vermette, P., Taylor, S., Dunstan, D., Meagher, L.: Control over PEGylated-liposome aggregation by NeutrAvidin-biotin interactions investigated by photon correlation spectroscopy. Langmuir 18, 505–511 (2002)CrossRefGoogle Scholar
  43. 43.
    Menger, F.M., Seredyuk, V.A., Yaroslavov, A.A.: Adhesive and anti-adhesive agents in giant vesicles. Angew. Chem.-Int. Edit. 41, 1350–1352 (2002)CrossRefGoogle Scholar
  44. 44.
    Berti, D., Baglioni, P., Bonaccio, S., Barsacchi-Bo, G., Luisi, P.L.: Base complementarity and nucleoside recognition in phosphatidylnucleoside vesicles. J. Phys. Chem. B 102, 303–308 (1998)CrossRefGoogle Scholar
  45. 45.
    Sideratou, Z., Foundis, J., Tsiourvas, D., Nezis, I.P., Papadimas, G., Paleos, C.M.: A novel dendrimeric “glue” for adhesion of phosphatidyl choline-based liposomes. Langmuir 18, 5036–5039 (2002)CrossRefGoogle Scholar
  46. 46.
    Marchi-Artzner, V., Gulik-Krzywicki, T., Guedeau-Boudeville, M.A., Gosse, C., Sanderson, J.M., Dedieu, J.C., Lehn, J.M.: Selective adhesion, lipid exchange and membrane-fusion processes between vesicles of various sizes bearing complementary molecular recognition groups. Chem. Phys. Chem. 2, 367–376 (2001)Google Scholar
  47. 47.
    Paleos, C.M., Sideratou, Z., Tsiourvas, D.: Mixed vesicles of didodecyldimethylammonium bromide with recognizable moieties at the interface. J. Phys. Chem. 100, 13898–13900 (1996)CrossRefGoogle Scholar
  48. 48.
    Constable, E.C., Meier, W., Nardin, C., Mundwiler, S.: Reversible metal-directed assembly of clusters of vesicles. Chem. Commun., 1483–1484 (1999)Google Scholar
  49. 49.
    Chiruvolu, S., Walker, S., Israelachvili, J., Schmitt, F.J., Leckband, D., Zasadzinski, J.A.: Higher-order self-assembly of vesicles by site-specific binding. Science 264, 1753–1756 (1994)CrossRefGoogle Scholar
  50. 50.
    NopplSimson, D.A., Needham, D.: Avidin-biotin interactions at vesicle surfaces: Adsorption and binding, cross-bridge formation, and lateral interactions. Biophys. J. 70, 1391–1401 (1996)CrossRefGoogle Scholar
  51. 51.
    Weikl, T.R., Groves, J.T., Lipowsky, R.: Pattern formation during adhesion of multicomponent membranes. Europhys. Lett. 59, 916–922 (2002)CrossRefGoogle Scholar
  52. 52.
    Voskuhl, J., Ravoo, B.J.: Molecular recognition of bilayer vesicles. Chem. Soc. Rev. 38, 495–505 (2009)CrossRefGoogle Scholar
  53. 53.
    Biancaniello, P.L., Crocker, J.C., Hammer, D.A., Milam, V.T.: DNA-mediated phase behavior of microsphere suspensions. Langmuir 23, 2688–2693 (2007)CrossRefGoogle Scholar
  54. 54.
    Mirkin, C.A., Letsinger, R.L., Mucic, R.C., Storhoff, J.J.: A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 382, 607–609 (1996)CrossRefGoogle Scholar
  55. 55.
    Valignat, M.P., Theodoly, O., Crocker, J.C., Russel, W.B., Chaikin, P.M.: Reversible self-assembly and directed assembly of DNA-linked micrometer-sized colloids. Proc. Natl. Acad. Sci. USA 102, 4225–4229 (2005)CrossRefGoogle Scholar
  56. 56.
    Biancaniello, P., Kim, A., Crocker, J.: Colloidal interactions and self-assembly using DNA hybridization. Phys. Rev. Lett. 94, 058302 (2005)CrossRefGoogle Scholar
  57. 57.
    Beales, P.A., Vanderlick, T.K.: Specific binding of different vesicle populations by the hybridization of membrane-anchored DNA. J. Phys. Chem. A 111, 12372–12380 (2007)CrossRefGoogle Scholar
  58. 58.
    Beales, P.A., Vanderlick, T.K.: DNA as Membrane-Bound Ligand-Receptor Pairs: Duplex Stability Is Tuned by Intermembrane Forces. Biophys. J. 96, 1554–1565 (2009)CrossRefGoogle Scholar
  59. 59.
    Stengel, G., Zahn, R., Hook, F.: DNA-induced programmable fusion of phospholipid vesicles. J. Am. Chem. Soc. 129, 9584–9585 (2007)CrossRefGoogle Scholar
  60. 60.
    Benkoski, J.J., Hook, F.: Lateral mobility of tethered vesicle - DNA assemblies. J. Phys. Chem. B 109, 9773–9779 (2005)CrossRefGoogle Scholar
  61. 61.
    Yoshina-Ishii, C., Boxer, S.G.: Arrays of mobile tethered vesicles on supported lipid bilayers. J. Am. Chem. Soc. 125, 3696–3697 (2003)CrossRefGoogle Scholar
  62. 62.
    Li, F., Pincet, F., Perez, E., Eng, W.S., Melia, T.B.J., Rothman, J.E., Tareste, D.: Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat. Struct. Mol. Biol. 14, 890–896 (2007)CrossRefGoogle Scholar
  63. 63.
    Svedhem, S., Pfeiffer, I., Larsson, C., Wingren, C., Borrebaeck, C., Hook, F.: Patterns of DNA-labeled and scFv-antibody-carrying lipid vesicles directed by material-specific immobilization of DNA and supported lipid bilayer formation on an Au/SiO2 template. Chembiochem. 4, 339–343 (2003)CrossRefGoogle Scholar
  64. 64.
    Stadler, B., Falconnet, D., Pfeiffer, I., Hook, F., Voros, J.: Micropatterning of DNA-tagged vesicles. Langmuir 20, 11348–11354 (2004)CrossRefGoogle Scholar
  65. 65.
    Hadorn, M., Eggenberger Hotz, P.: DNA-Mediated Self-Assembly of Artificial Vesicles. PLoS One 5 5, e9886 (2010)CrossRefGoogle Scholar
  66. 66.
    Pautot, S., Frisken, B.J., Weitz, D.A.: Engineering asymmetric vesicles. Proc. Natl. Acad. Sci. USA 100, 10718–10721 (2003)CrossRefGoogle Scholar
  67. 67.
    Hadorn, M., Burla, B., Eggenberger Hotz, P.: Towards tailored communication networks in assemblies of artificial cells. In: Korb, K., Randall, M., Hendtlass, T. (eds.) ACAL 2009. LNCS, vol. 5865, pp. 126–135. Springer, Heidelberg (2009)CrossRefGoogle Scholar
  68. 68.
    Hadorn, M., Eggenberger Hotz, P.: Multivesicular assemblies as real-world testbeds for embryogenic evolutionary systems. In: Korb, K., Randall, M., Hendtlass, T. (eds.) ACAL 2009. LNCS, vol. 5865, pp. 169–178. Springer, Heidelberg (2009)CrossRefGoogle Scholar
  69. 69.
    Träuble, H., Grell, E.: Carriers and specificity in membranes. IV. Model vesicles and membranes. The formation of asymmetrical spherical lecithin vesicles. Neurosciences Research Program bulletin 9, 373–380 (1971)Google Scholar
  70. 70.
    Licata, N.A., Tkachenko, A.V.: Errorproof programmable self-assembly of DNA-nanoparticle clusters. Physical Review E (Statistical, Nonlinear, and Soft Matter Physics) 74, 41406 (2006)CrossRefGoogle Scholar
  71. 71.
    Green, N.M.: Avidin and streptavidin. Method Enzymol. 184, 51–67 (1990)CrossRefGoogle Scholar
  72. 72.
    Singer, S.J., Nicolson, G.L.: Fluid mosaic model of structure of cell-membranes. Science 175, 720–731 (1972)CrossRefGoogle Scholar
  73. 73.
    Burridge, K.A., Figa, M.A., Wong, J.Y.: Patterning adjacent supported lipid bilayers of desired composition to investigate receptor-ligand binding under shear flow. Langmuir 20, 10252–10259 (2004)CrossRefGoogle Scholar
  74. 74.
    Pappas, D., Wang, K.: Cellular separations: A review of new challenges in analytical chemistry. Anal. Chim. Acta 601, 26–35 (2007)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Maik Hadorn
    • 1
  • Peter Eggenberger Hotz
    • 2
  1. 1.Department of Informatics, Artificial Intelligence LaboratoryUniversity of ZurichZurichSwitzerland
  2. 2.The Mærsk Mc-Kinney Møller InstituteUniversity of Southern DenmarkOdense MDenmark

Personalised recommendations