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. 2000 Apr;78(4):1681–1697. doi: 10.1016/S0006-3495(00)76720-8

The phase behavior of cationic lipid-DNA complexes.

S May 1, D Harries 1, A Ben-Shaul 1
PMCID: PMC1300765  PMID: 10733951

Abstract

We present a theoretical analysis of the phase behavior of solutions containing DNA, cationic lipids, and nonionic (helper) lipids. Our model allows for five possible structures, treated as incompressible macroscopic phases: two lipid-DNA composite (lipoplex) phases, namely, the lamellar (L(alpha)(C)) and hexagonal (H(II)(C)) complexes; two binary (cationic/neutral) lipid phases, that is, the bilayer (L(alpha)) and inverse-hexagonal (H(II)) structures, and uncomplexed DNA. The free energy of the four lipid-containing phases is expressed as a sum of composition-dependent electrostatic, elastic, and mixing terms. The electrostatic free energies of all phases are calculated based on Poisson-Boltzmann theory. The phase diagram of the system is evaluated by minimizing the total free energy of the three-component mixture with respect to all the compositional degrees of freedom. We show that the phase behavior, in particular the preferred lipid-DNA complex geometry, is governed by a subtle interplay between the electrostatic, elastic, and mixing terms, which depend, in turn, on the lipid composition and lipid/DNA ratio. Detailed calculations are presented for three prototypical systems, exhibiting markedly different phase behaviors. The simplest mixture corresponds to a rigid planar membrane as the lipid source, in which case, only lamellar complexes appear in solution. When the membranes are "soft" (i.e., low bending modulus) the system exhibits the formation of both lamellar and hexagonal complexes, sometimes coexisting with each other, and with pure lipid or DNA phases. The last system corresponds to a lipid mixture involving helper lipids with strong propensity toward the inverse-hexagonal phase. Here, again, the phase diagram is rather complex, revealing a multitude of phase transitions and coexistences. Lamellar and hexagonal complexes appear, sometimes together, in different regions of the phase diagram.

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Selected References

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  1. Battersby B. J., Grimm R., Huebner S., Cevc G. Evidence for three-dimensional interlayer correlations in cationic lipid-DNA complexes as observed by cryo-electron microscopy. Biochim Biophys Acta. 1998 Jul 17;1372(2):379–383. doi: 10.1016/s0005-2736(98)00062-5. [DOI] [PubMed] [Google Scholar]
  2. Boukhnikachvili T., Aguerre-Chariol O., Airiau M., Lesieur S., Ollivon M., Vacus J. Structure of in-serum transfecting DNA-cationic lipid complexes. FEBS Lett. 1997 Jun 9;409(2):188–194. doi: 10.1016/s0014-5793(97)00505-x. [DOI] [PubMed] [Google Scholar]
  3. Chen Z., Rand R. P. Comparative study of the effects of several n-alkanes on phospholipid hexagonal phases. Biophys J. 1998 Feb;74(2 Pt 1):944–952. doi: 10.1016/S0006-3495(98)74017-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Felgner P. L., Gadek T. R., Holm M., Roman R., Chan H. W., Wenz M., Northrop J. P., Ringold G. M., Danielsen M. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7413–7417. doi: 10.1073/pnas.84.21.7413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Felgner P. L. Nonviral strategies for gene therapy. Sci Am. 1997 Jun;276(6):102–106. doi: 10.1038/scientificamerican0697-102. [DOI] [PubMed] [Google Scholar]
  6. Gawrisch K., Parsegian V. A., Hajduk D. A., Tate M. W., Graner S. M., Fuller N. L., Rand R. P. Energetics of a hexagonal-lamellar-hexagonal-phase transition sequence in dioleoylphosphatidylethanolamine membranes. Biochemistry. 1992 Mar 24;31(11):2856–2864. doi: 10.1021/bi00126a003. [DOI] [PubMed] [Google Scholar]
  7. Harries D., May S., Gelbart W. M., Ben-Shaul A. Structure, stability, and thermodynamics of lamellar DNA-lipid complexes. Biophys J. 1998 Jul;75(1):159–173. doi: 10.1016/S0006-3495(98)77503-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Helfrich W. Elastic properties of lipid bilayers: theory and possible experiments. Z Naturforsch C. 1973 Nov-Dec;28(11):693–703. doi: 10.1515/znc-1973-11-1209. [DOI] [PubMed] [Google Scholar]
  9. Hope M. J., Mui B., Ansell S., Ahkong Q. F. Cationic lipids, phosphatidylethanolamine and the intracellular delivery of polymeric, nucleic acid-based drugs (review). Mol Membr Biol. 1998 Jan-Mar;15(1):1–14. doi: 10.3109/09687689809027512. [DOI] [PubMed] [Google Scholar]
  10. Huebner S., Battersby B. J., Grimm R., Cevc G. Lipid-DNA complex formation: reorganization and rupture of lipid vesicles in the presence of DNA as observed by cryoelectron microscopy. Biophys J. 1999 Jun;76(6):3158–3166. doi: 10.1016/S0006-3495(99)77467-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hui S. W., Langner M., Zhao Y. L., Ross P., Hurley E., Chan K. The role of helper lipids in cationic liposome-mediated gene transfer. Biophys J. 1996 Aug;71(2):590–599. doi: 10.1016/S0006-3495(96)79309-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Koltover I., Salditt T., Rädler J. O., Safinya C. R. An inverted hexagonal phase of cationic liposome-DNA complexes related to DNA release and delivery. Science. 1998 Jul 3;281(5373):78–81. doi: 10.1126/science.281.5373.78. [DOI] [PubMed] [Google Scholar]
  13. Kozlov M. M., Leikin S., Rand R. P. Bending, hydration and interstitial energies quantitatively account for the hexagonal-lamellar-hexagonal reentrant phase transition in dioleoylphosphatidylethanolamine. Biophys J. 1994 Oct;67(4):1603–1611. doi: 10.1016/S0006-3495(94)80633-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Leikin S., Kozlov M. M., Fuller N. L., Rand R. P. Measured effects of diacylglycerol on structural and elastic properties of phospholipid membranes. Biophys J. 1996 Nov;71(5):2623–2632. doi: 10.1016/S0006-3495(96)79454-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. May S., Ben-Shaul A. DNA-lipid complexes: stability of honeycomb-like and spaghetti-like structures. Biophys J. 1997 Nov;73(5):2427–2440. doi: 10.1016/S0006-3495(97)78271-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Parsegian V. A., Gingell D. On the electrostatic interaction across a salt solution between two bodies bearing unequal charges. Biophys J. 1972 Sep;12(9):1192–1204. doi: 10.1016/S0006-3495(72)86155-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pitard B., Oudrhiri N., Vigneron J. P., Hauchecorne M., Aguerre O., Toury R., Airiau M., Ramasawmy R., Scherman D., Crouzet J. Structural characteristics of supramolecular assemblies formed by guanidinium-cholesterol reagents for gene transfection. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2621–2626. doi: 10.1073/pnas.96.6.2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rädler J. O., Koltover I., Salditt T., Safinya C. R. Structure of DNA-cationic liposome complexes: DNA intercalation in multilamellar membranes in distinct interhelical packing regimes. Science. 1997 Feb 7;275(5301):810–814. doi: 10.1126/science.275.5301.810. [DOI] [PubMed] [Google Scholar]
  19. Safinya CR, Sirota EB, Roux D, Smith GS. Universality in interacting membranes: The effect of cosurfactants on the interfacial rigidity. Phys Rev Lett. 1989 Mar 6;62(10):1134–1137. doi: 10.1103/PhysRevLett.62.1134. [DOI] [PubMed] [Google Scholar]
  20. Sternberg B., Sorgi F. L., Huang L. New structures in complex formation between DNA and cationic liposomes visualized by freeze-fracture electron microscopy. FEBS Lett. 1994 Dec 19;356(2-3):361–366. doi: 10.1016/0014-5793(94)01315-2. [DOI] [PubMed] [Google Scholar]
  21. Szleifer I, I, Kramer D, Ben-Shaul A, Roux D, Gelbart WM. Curvature elasticity of pure and mixed surfactant films. Phys Rev Lett. 1988 May 9;60(19):1966–1969. doi: 10.1103/PhysRevLett.60.1966. [DOI] [PubMed] [Google Scholar]
  22. Tarahovsky T. S., Khusainova R. S., Gorelov A. V., Nicolaeva T. I., Deev A. A., Dawson A. K., Ivanitsky G. R. DNA initiates polymorphic structural transitions in lecithin. FEBS Lett. 1996 Jul 22;390(2):133–136. doi: 10.1016/0014-5793(96)00643-6. [DOI] [PubMed] [Google Scholar]
  23. Templeton N. S., Lasic D. D., Frederik P. M., Strey H. H., Roberts D. D., Pavlakis G. N. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol. 1997 Jul;15(7):647–652. doi: 10.1038/nbt0797-647. [DOI] [PubMed] [Google Scholar]
  24. Wagner K., Keyes E., Kephart T. W., Edwards G. Analytical Debye-Huckel model for electrostatic potentials around dissolved DNA. Biophys J. 1997 Jul;73(1):21–30. doi: 10.1016/S0006-3495(97)78043-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zuidam N. J., Hirsch-Lerner D., Margulies S., Barenholz Y. Lamellarity of cationic liposomes and mode of preparation of lipoplexes affect transfection efficiency. Biochim Biophys Acta. 1999 Jul 15;1419(2):207–220. doi: 10.1016/s0005-2736(99)00069-3. [DOI] [PubMed] [Google Scholar]

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