Physicochemical Profiling of Surfactant-Induced Membrane Dynamics

Letter pubs.acs.org/JPCL

Physicochemical Profiling of Surfactant-Induced Membrane Dynamics in a Cell-Sized Liposome Tsutomu Hamada,† Hideyuki Hagihara,† Masamune Morita,† Mun’delanji C. Vestergaard,† Yoshio Tsujino,‡ and Masahiro Takagi*,† †

School of Materials Science, Japan Advanced Institute of Science and Technology, 1−1 Asahidai, Nomi, Ishikawa 923-1292, Japan Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan

‡

S Supporting Information *

ABSTRACT: We used a cell-sized model system, giant liposomes, to investigate the interaction between lipid membranes and surfactants, and the membrane transformation during the solubilization process was captured in real time. We found that there are four distinct dynamics in surfactant-induced membrane deformation: an episodic increase in the membrane area prior to pore-forming associated shrinkage (Dynamics A), fission into many small liposomes (Dynamics B), the formation of multilamellar vesicles and peeling (Dynamics C), and bursting (Dynamics D). Classification of the diversity of membrane dynamics may contribute to a better understanding of the physicochemical mechanism of membrane solubilization induced by various surfactants.

SECTION: Surfactants, Membranes

I

increase in vesicular size. Second, the saturated membranes disintegrate because of the formation of lipid-surfactant mixed micelles. Finally, all of the membrane material is converted into mixed micelles. However, an LUV system does not give detailed information on the vesicular shapes of individual liposomes during the solubilization process in real time. It is important to study the profiles of shape-transformation patterns of liposomes to explore possible implications in membranesurfactant systems. Previously, we achieved the real-time observation of the overall dynamical process of membrane solubilization induced by the nonionic surfactant Triton X-100 at the level of single vesicles using a cell-sized model system, homogeneous DOPC liposome.28 After the application of Triton X-100, liposomes acquired a temporary increase in excess membrane area that allowed large vesicular deformations, followed by pore-forming associated shrinkage. This trend was in agreement with studies using LUV systems.23,25−27 Moreover, microscopic observations clearly revealed that vesicles show two types of poreforming shrinkage: rhythmic-pore and continuous-pore.28 In this study, we used this cell-sized model system for the physicochemical profiling of membrane dynamics induced by various surfactants. The results showed that vesicles exhibit four distinct deformation patterns depending on the surfactants added and their concentrations.

t is important to understand the physicochemical mechanisms that govern the structural stability and dynamics of a cellular interface with a lipid bilayer membrane. Lipids, which are a main component of biological membranes, exhibit selforganized vesicular structures, called liposomes, which essentially have a bilayer structure similar to that of living cell membranes.1 In fact, cell-sized liposomes have been actively studied as cell models due to their similarities to natural cell structures in terms of size and membrane composition.2−4 Becasue they are large enough to allow direct microscopic observation of the membrane behavior of individual vesicles, this cell-sized model system could help us to better understand the mechanical properties of biological membranes. Investigations have been carried out on morphological dynamics in response to various stimuli, such as temperature,5,6 light,7−13 osmotic stress,14−17 pH,18 electric fields,19,20 and the addition of peptides.21,22 Surfactants with amphiphilic properties have frequently been used for the solubilization of membrane components, which facilitates the extraction of membrane proteins from cellular membranes. 23,24 Solubilization, including the stability of membrane pores, is also essential for the development of controlled-release systems, such as for drug-delivery.8 For a better understanding of the interaction between surfactants and biomembranes, studies with liposomal model membrane systems are invaluable. Previous studies on the surfactantinduced solubilization of submicrometer large unilamellar vesicles (LUVs) mainly detected changes in the average size of a liposome population.23,25−27 On the basis of these experimental results, the following model was proposed. First, the incorporation of surfactants into membranes leads to an © 2012 American Chemical Society

Received: December 6, 2011 Accepted: January 17, 2012 Published: January 17, 2012 430

dx.doi.org/10.1021/jz2016044 | J. Phys. Chem. Lett. 2012, 3, 430−435

The Journal of Physical Chemistry Letters

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Figure 1. Microscopic image sequences (a−d) of liposomal transformation induced by surfactants, together with schematics (e). The bars represent 10 μm. Added surfactants were triton X-100 (10% w/w) (a), polyoxyethylene-polyoxypropylene decyl ethers (10% w/w) (b), polyol coconut fatty acid ester (25% w/w) (c), and triton X-100 (100% w/w) (d).

Figure 1 shows an example of the dynamic transformation of liposomes after the introduction of various surfactants (Supporting Information). The time development of the long-axis length (L) divided by the initial diameter (D) of liposomes was measured (Figure 2) to give the degree of deformation.29 We found that there are four distinct membrane deformation pathways (Dynamics A, B, C, and D, as shown in Figure 1a−d, respectively). In Dynamics A−C, liposomes exhibit morphological changes prior to pore-forming associated shrinkage. Conversely, in Dynamics D, liposomes suddenly burst into submicrometer aggregates such as micelles without pore-forming associated shrinkage. In this case, liposomes remained essentially unchanged in size until they burst (Figure 2d). In Dynamics A (Figure 1a,e), after the introduction of surfactants, fluctuation of the vesicular membrane was enhanced, and the liposomes then invaginated to form numerous membrane tubes or vesicles inside the spherical liposomes. The daughter vesicles were often observed to be separated from the membrane surface of the mother liposomes. Over time, this membrane fluctuation gradually decreased until a completely spherical structure was recovered. The liposomes then generated a pore within the bilayer and shrank. The time-dependent change in L/D (Figure 2a, see also the Supporting

Information) indicates that the membrane area gradually increased and then decreased during vesicle deformation. In Dynamics B (Figure 1b and e), upon treatment with surfactants, liposomes started to fluctuate, followed by the appearance of thin membrane tubes in the inner water pool, similar to Dynamics A. Because of crowding caused by growth of the tubes, the outer membrane surface deformed further and exhibited fission into many small liposomes. The resulting small liposomes then underwent pore-forming associated shrinking dynamics. The time-dependent change in L/D (Figure 2b, see also the Supporting Information) shows that the projected area of liposomes increased gradually during the formation of internal tubes and then suddenly increased rapidly due to the large deformation prior to fission. Therefore, in contrast with Dynamics A, Dynamics B did not return to the initial spherical state after deformation but rather exhibited fission into many spherical liposomes. To characterize the two dynamics, we measured the initial membrane surface area and vesicular volume as well as the same parameters just before the onset of poreforming associated shrinkage in Dynamics A and B. In Dynamics A, the surface area and vesicular volume were essentially constant before and after the deformation process (Figure 2e,f). 431



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Figure 2. (a−d) Typical results of the time-development of the long-axis length (L) divided by the initial diameter (D) of liposomes during each deformation dynamics. Time zero indicates the time at which surfactants were applied to the liposomes. Added surfactants were ethanol (100% w/w) (a), polyoxethylene (caprylate/caprate) glycerides (5% w/w) (b), polyol coconut fatty acid ester (25% w/w) (c), and SDS (10% w/w) (d). (e−h) Distributions of the changes in volume and surface area (volume or area of spherical vesicles after deformation divided by that before deformation) for Dynamics A and B. Note that in Dynamics B we measured the diameter of an initial spherical vesicle and those of several small spherical vesicles produced after fission. The volume and surface of vesicles after deformation were calculated as the sum of these small vesicles. (i) Time elapsed for the complete transition of four vesicular deformation dynamics. Horizontal lines represent the standard deviation. N = 40 (Dynamics A), 13 (Dynamics B), 4 (Dynamics C), and 22 (Dynamics D).

associated shrinkage dynamics.28 There are two distinct pore dynamics in the shrinkage process (Figure 3a): either an open pore remains in a vesicular membrane until the vesicle becomes smaller and disappears (continuous-pore) or a transient pore is generated in a repetitive manner (rhythmic-pore).28 The timedependent change in the liposomal surface area is shown in Figure 3b. The speed of the reduction in liposome size during continuous-pore shrinkage is faster than that associated with rhythmic-pore shrinkage. The results observed for various surfactants are summarized in Table 1. With Triton X-100 and Tween 20, a high concentration of surfactants induced Dynamics D. In contrast, Dynamics A was observed at low concentrations. These trends can probably be attributed to the speed balance between the incorporation of surfactants into the outer leaflet of the bilayer and their flip-flop motion from the outer to inner leaflet. When surfactant molecules are gradually incorporated in the outer leaflet, some molecules transfer to the inner leaflet (flip-flop) to achieve an equilibrium distribution, which results in an increase in the total surface area of the bilayer membrane. However, if the speed of incorporation is much faster than that of the flipflop, such as with the application of large amounts of surfactant,

Conversely, Dynamics B showed an increase in surface area without a change in volume (Figure 2g,h). In Dynamics C (Figure 1c,e), after an increase in membrane fluctuation, some lamellar structures appeared in the vesicular space, probably because of invagination. The lamella was organized to form multilamellar liposomes. The outer layer then peeled, and the inner vesicle was exposed. This process was repeated many times.30 Each of the resulting vesicles exhibited pore-forming associated shrinkage. The ratio of L/D showed slight variation over time but essentially remained constant until the outer layer peeled away (Figure 2c, see also the Supporting Information). We expected the total membrane area to increase by the formation of an inner multilayer. Next, we analyzed the speed of solubilization. Figure 2i shows the elapsed time in each deformation process, that is, the time interval in which liposomes generate microscopic pores after the application of surfactants. For Dynamics A, the time elapsed (149 ± 179 s) was shorter than that in Dynamics B (315 ± 352 s), and Dynamics C required the most time (972 ± 327 s). In Dynamics D, liposomes burst soon after the application of surfactants (62 ± 46 s). After these deformation processes (Dynamics A−C), liposomes exhibited pore-forming 432



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Table 1. Summarized Results of Deformation Dynamics and Pore-Forming Associated Shrinkage for Each Surfactanta surfactants Triton X-100 (100% w/w) Triton X-100 (10% w/w) Triton X-100 (5% w/w) Triton X-100 (1% w/w) Tween 20 (100% w/w) Tween 20 (10% w/w) Tween 20 (5% w/w) Tween 80 (100% w/w) Tween 80 (10% w/w) SDS (10% w/w) cetyltrimethylammonium bromide (10% w/w) ethanol (100% w/w) ethanol (10% w/w) polyol coconut fatty acid ester (25% w/w) polyoxyethylene-polyoxypropylene decyl ethers (10% w/w) polyoxyethylene-polyoxypropylene decyl ethers (5% w/w) DL-pyrrolidonecarboxylic acid salt of L-cocoyl arginine ethyl ester (1% w/w) polyoxethylene (caprylate/caprate) glycerides (100% w/w) polyoxethylene (caprylate/caprate) glycerides (25% w/w) polyoxethylene (caprylate/caprate) glycerides (5% w/w)

Figure 3. (a) Microscopic image sequences of pore-forming associated shrinkage. Arrows point to the pore formed within the membrane. The bars represent 10 μm. Triton X-100 (1% w/w) and ethanol (100% w/w) were applied for continuous and rhythmic pore, respectively. (b) Time-dependent change in surface area during continuous-pore (open square and triangle) and rhythmic-pore (gray circle and diamond) shrinkage. Surface area was divided by the initial one obtained before pore opening. Added surfactants were triton X-100 (10% w/w) (open square and triangle) and polyol coconut fatty acid ester (5% w/w) (gray circle and diamond).

deformation dynamics D A A A D D A C C D D

pore-forming associated shrinkage C-Pore C-Pore C-Pore

R-Pore R-Pore R-Pore

A No dynamics C

R-Pore R-Pore

B

R-Pore

B

R-Pore

A

R-Pore

A

C-Pore

A

C-Pore

B

R-Pore

a

C-Pore and R-Pore indicate continuous-pore and rhythmic-pore, respectively. To determine the pattern of dynamics, we counted n > 30 liposomes for each treatment.

have affected the incorporation of surfactants into membranes and the transfer rate between the outer and inner leaflets of the bilayer, resulting in the different deformation dynamics.33 In addition, there is a relationship between the type of deformation and the shrinkage dynamics. After deformation in Dynamics A, liposomes exhibited continuous-pore or rhythmic-pore shrinkage. In contrast, Dynamics B and C led to only rhythmic-pore shrinkage. The connection between deformation and shrinkage dynamics may be associated with the speed of disintegration. The speed of deformation dynamics is in the order A > B > C, and the speed of continuous-pore shrinkage is greater than that of rhythmic-pore shrinkage. The slow deformation in Dynamics B and C lead to the slow rhythmic-pore shrinkage, whereas the fast Dynamics A lead to fast continuous-pore shrinkage. Some investigations with giant vesicles have shown direct image sequences of surfactant-induced membrane transformation.34,35 Notably, in addition to the present observed rhythmic- and continuous-pore-forming behavior of zwitterionic lipid DOPC liposomes, Nomura et al. reported that liposomes with charged lipids showed inside-out inversion and opening-up solubilization.36 Tomita et al. also reported that giant multilamellar liposomes showed different solubilization patterns.37 Multicomponent raft-exhibiting liposomes have been reported to show budding deformations when subjected to surfactants.15,38 Recently, we have developed a method for the characterization of membrane dynamics patterns in the presence of chemicals, such as toxic peptides.21 This physicochemical profiling of membrane dynamics in a cell-sized model system may lead to opportunities for studying cellular damage caused by external stimuli.

then the difference in the amount of molecules between leaflets is increased, which would further increase the spontaneous curvature of the membrane. Highly increased spontaneous curvature leads to the bursting of vesicles. Sudbrack et al. reported that SDS with a low rate of flip-flop caused vesicle bursting, which agrees with our experimental results (Dynamics D).31 In addition, the formation of inner tubular structure in the vesicle interior suggests that the vesicles acquired negative spontaneous curvature.32 A change in the spontaneous curvature is possibly attributed to the osmotic imbalance between the initial vesicle suspension and the surfactant solutions added. Previously, we reported that sugar-induced osmotic pressure caused the formation of membrane tubes inside vesicles.7 However, a variety of deformation patterns reported here (Dynamics A−D) have not been observed in the presence of osmotic pressure only. Therefore, we propose that the formation of inner tubes or vesicles is caused by osmotic imbalance of surfactants across the membranes. The subsequent deformation dynamics is essentially attributed to the solubilization effect of surfactants. It may be useful to note that there are clear differences in vesicular transformation between Tween 20 and Tween 80 because although they have the same hydrophilic moiety, they have a different hydrophobic group (monolaurate or monooleate chain for Tween 20 or Tween 80, respectively). Tween 20 induced Dynamics D (100 and 10% w/w) and A (5% w/w), whereas Tween 80 caused Dynamics C (100 and 10% w/w). The difference in the hydrophobic groups may 433



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(10) Hamada, T.; Sato, Y. T.; Yoshikawa, K.; Nagasaki, T. Reversible Photoswitching in a Cell-Sized Vesicle. Langmuir 2005, 21, 7626− 7628. (11) Petrov, P. G.; Lee, J. B.; Dobereiner, H. G. Coupling Chemical Reactions to Membrane Curvature: A Photochemical Morphology Switch. Europhys. Lett. 1999, 48, 435−441. (12) Karatekin, E.; Sandre, O.; Guitouni, H.; Borghi, N.; Puech, P. H.; Brochard-Wyart, F. Cascades of Transient Pores In Giant Vesicles: Line Tension and Transport. Biophys. J. 2003, 84, 1734−1749. (13) Yasuhara, K.; Sasaki, Y.; Kikuchi, J. A Photo-Responsive Cholesterol Capable of Inducing a Morphological Transformation of the Liquid-Ordered Microdomain in Lipid Bilayers. Colloid Polym. Sci. 2008, 286, 1675−1680. (14) Ohno, M.; Hamada, T.; Takiguchi, K.; Homma, M. Dynamic Behavior of Giant Liposomes at Desired Osmotic Pressures. Langmuir 2009, 25, 11680−11685. (15) Hamada, T.; Miura, Y.; Ishii, K.; Araki, S.; Yoshikawa, K.; Vestergaard, M.; Takagi, M. Dynamic Processes in Endocytic Transformation of a Raft-Exhibiting Giant Liposome. J. Phys. Chem. B 2007, 111, 10853−10857. (16) Hotani, H. Transformation Pathways of Liposomes. J. Mol. Biol. 1984, 178, 113−120. (17) Yanagisawa, M.; Imai, M.; Taniguchi, T. Shape Deformation of Ternary Vesicles Coupled with Phase Separation. Phys. Rev. Lett. 2008, 100, 148102. (18) Khalifat, N.; Puff, N.; Bonneau, S.; Fournier, J. B.; Angelova, M. I. Membrane Deformation under Local pH Gradient: Mimicking Mitochondrial Cristae Dynamics. Biophys. J. 2008, 95, 4924−4933. (19) Dimova, R.; Riske, K. A.; Aranda, S.; Bezlyepkina, N.; Knorr, R. L.; Lipowsky, R. Giant Vesicles in Electric Fields. Soft Matter 2007, 3, 817−827. (20) Dimova, R.; Bezlyepkina, N.; Jordo, M. D.; Knorr, R. L.; Riske, K. A.; Staykova, M.; Vlahovska, P. M.; Yamamoto, T.; Yang, P.; Lipowsky, R. Vesicles in Electric Fields: Some Novel Aspects of Membrane Behavior. Soft Matter 2009, 5, 3201−3212. (21) Morita, M.; Vestergaard, M.; Hamada, T.; Takagi, M. Real-Time Observation of Model Membrane Dynamics Induced by Alzheimer’s Amyloid Beta. Biophys. Chem. 2010, 147, 81−86. (22) Sens, P.; Johannes, L.; Bassereau, P. Biophysical Approaches to Protein-Induced Membrane Deformations in Trafficking. Curr. Opin. Cell. Biol. 2008, 20, 476−482. (23) Kragh-Hansen, U.; le Maire, M.; Moller, J. V. The Mechanism of Detergent Solubilization of Liposomes and Protein-Containing Membranes. Biophys. J. 1998, 75, 2932−2946. (24) Knol, J.; Sjollema, K.; Poolman, B. Detergent-Mediated Reconstitution of Membrane Proteins. Biochemistry 1998, 37, 16410− 16415. (25) Paternostre, M. T.; Roux, M.; Rigaud, J. L. Mechanisms of Membrane Protein Insertion into Liposomes During Reconstitution Procedures Involving the Use of Detergents. Biochemistry 1988, 27, 2668−2677. (26) Delamaza, A.; Parra, J. L. Vesicle-Micelle Structural Transitions of Phospholipid-Bilayers and Sodium Dodecyl-Sulfate. Langmuir 1995, 11, 2435−2441. (27) Almgren, M. Mixed Micelles and Other Structures in the Solubilization of Bilayer Lipid Membranes by Surfactants. Biochim. Biophys. Acta 2000, 1508, 146−163. (28) Hamada, T.; Hirabayashi, Y.; Ohta, T.; Takagi, M. Rhythmic Pore Dynamics in a Shrinking Lipid Vesicle. Phys. Rev. E 2009, 80, 051921. (29) Kato, A.; Shindo, E.; Sakaue, T.; Tsuji, A.; Yoshikawa, K. Conformational Transition of Giant DNA in a Confined Space Surrounded by a Phospholipid Membrane. Biophys. J. 2009, 97, 1678−86. (30) Hamada, T.; Yoshikawa, K. Peeling Kinetics of Giant Multilamellar Vesicles on a Solid-Liquid Interface. Chem. Phys. Lett. 2004, 396, 303−307.

EXPERIMENTAL METHODS Cell-sized giant vesicles were prepared with 0.2 mM 1,2dioleoyl-sn-glycero-3-phosphocholine (DOPC) with 2 mol % N-(rhodamine red-X)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (rho-PE). We constructed an observation chamber with two compartments separated by a porous filter,15,28 which allowed the vesicles to interact with the added surfactants. (The surfactants used in this study are listed in the Supporting Information.) Timedependent changes in membrane morphology were observed using a fluorescence microscope.

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ASSOCIATED CONTENT

* Supporting Information S

Experimental methods, list of the surfactants used in this study, and other data sets of the time-development of L/D. This material is available free of charge via the Internet at http:// pubs.acs.org

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +81-761-51-1650. Fax: +81761-51-1525. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by KAKENHI Grants-in-Aid for Scientific Research B and C and Young Scientists B from JSPS, on Priority Area “Soft Matter Physics” from MEXT of Japan, and by a Sunbor Grant from the Suntory Foundation for Life Sciences and third Mandom International Research Grants on Alternative to Animal Experiments.

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REFERENCES

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Physicochemical Profiling of Surfactant-Induced Membrane Dynamics

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