Non-lamellar lipid liquid crystalline structures at interfaces

CIS-01497; No of Pages 13 Advances in Colloid and Interface Science xxx (2014) xxx–xxx

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Non-lamellar lipid liquid crystalline structures at interfaces Debby P. Chang a,1, Justas Barauskas b,c, Aleksandra P. Dabkowska a,d, Maria Wadsäter a, Fredrik Tiberg a,b, Tommy Nylander a,d,⁎ a

Physical Chemistry, Department of Chemistry, Lund University, POB 124, 221 00 Lund, Sweden Camurus AB, Ideon Science Park, Gamma Building, Sölvegatan 41, SE-22379 Lund, Sweden Biomedical Science, Faculty of Health and Society, Malmö University, SE-20506 Malmö, Sweden d The Nanometer Structure Consortium (nmC@LU), Lund University, P.O. Box 118, SE-22100 Lund, Sweden b c

a r t i c l e

i n f o

Available online xxxx Keywords: Liquid crystalline nanoparticles Cubosomes Drug delivery Interfacial properties Lipid liquid crystalline structure

a b s t r a c t The self-assembly of lipids leads to the formation of a rich variety of nano-structures, not only restricted to lipid bilayers, but also encompassing non-lamellar liquid crystalline structures, such as cubic, hexagonal, and sponge phases. These non-lamellar phases have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Consequently, they are of great interest for their potential as delivery systems in pharmaceutical, food and cosmetic applications. The compartmentalizing nature of these phases features mono- or bicontinuous networks of both hydrophilic and hydrophobic domains. To utilize these non-lamellar liquid crystalline structures in biomedical devices for analyses and drug delivery, it is crucial to understand how they interact with and respond to different types of interfaces. Such non-lamellar interfacial layers can be used to entrap functional biomolecules that respond to lipid curvature as well as the confinement. It is also important to understand the structural changes of deposited lipid in relation to the corresponding bulk dispersions. They can be controlled by changing the lipid composition or by introducing components that can alter the curvature or by deposition on nano-structured surface, e.g. vertical nano-wire arrays. Progress in the area of liquid crystalline lipid based nanoparticles opens up new possibilities for the preparation of well-defined surface films with well-defined nano-structures. This review will focus on recent progress in the formation of non-lamellar dispersions and their interfacial properties at the solid/liquid and biologically relevant interfaces. © 2014 Published by Elsevier B.V.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Lipid liquid crystalline phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Nano-particle dispersion of lipid liquid crystalline phases . . . . . . . . . . . . . . . . . 1.3. Lipid liquid crystalline phases deposited on surfaces . . . . . . . . . . . . . . . . . . . 2. Solid–liquid interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Adsorption of LCNPs at solid interfaces — effect of surface properties . . . . . . . . . . . . 2.2. Adsorption of LCNPs at solid interfaces — effect of particle composition and solution conditions 2.3. LCNP interactions with models of biological interfaces . . . . . . . . . . . . . . . . . . 3. Structural characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Organization of the adsorbed layer . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The internal structure of the layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Applications and future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Physical Chemistry, Department of Chemistry, Lund University, POB 124, 221 00 Lund, Sweden. E-mail address: [email protected] (T. Nylander). 1 Present affiliation: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080, USA.

http://dx.doi.org/10.1016/j.cis.2014.11.003 0001-8686/© 2014 Published by Elsevier B.V.

Please cite this article as: Chang DP, et al, Non-lamellar lipid liquid crystalline structures at interfaces, Adv Colloid Interface Sci (2014), http:// dx.doi.org/10.1016/j.cis.2014.11.003

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1. Introduction The self-association of lipids, driven by the minimization of the contact between the hydrophobic regions with the aqueous phase and balanced by headgroup (repulsive) interactions and packing constrains of acyl chains, gives rise to rich variety of phases (Fig. 1) [1–3]. The nanostructures that form depend on the lipid nature, mixture composition and external conditions such as temperature. 1.1. Lipid liquid crystalline phases The assembly of polar lipids and their rich lyotropic phase behavior with 1D, 2D or 3D periodic liquid crystalline (LC) structures was to a large extent revealed in the pioneering works of Luzzati and colleagues in France [4] and Fontell, Larsson and colleagues in Sweden [5,6] from the late 1960s. Early on, many phospholipids, such as phosphatidylcholines, were found to spontaneously form lipid bilayers in aqueous dispersions under pH and ionic strength similar to that of biological systems. However, it was also observed that a variety of lipids such as cardiolipin [7], phosphatidylinositol (PI) [8,9] and phosphatidylethanolamine (PE) [10] form non-bilayer lipid phases, e.g. (reverse) hexagonal and cubic phases [11]. In particular, the non-lamellar phase based LC structures have been the focus of great interest and study in the last two decades as they have also been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity [12]. Non-lamellar LC structures, such as cubic, hexagonal and sponge phases, generally have much higher surface area per volume than micellar and lamellar structures and may solubilize hydrophobic, hydrophilic and also amphiphilic molecules [13–20]. 1.2. Nano-particle dispersion of lipid liquid crystalline phases Bulk lipid liquid crystalline phases can be dispersed into colloidal particles under excess water conditions. Bangham and colleagues first demonstrated dispersions of lamellar phases in the 1960s [21], and today vesicles and liposomes are often used for a range of applications in the development of formulations for drug delivery, food, and consumer products as well as models for biomembranes. Liquid crystalline nanoparticles of non-lamellar geometry were probably first observed in a light microscopy study of fat digestion in the late 1970s [22]. However,

oil-in-water

only later was it realized that these aggregates had a bicontinuous cubic structure. Buchheim and Larsson reported how to prepare the first versions of partially-stabilized fragmented non-lamellar, cubic phase particles, more than two decades ago by using dispersions of unsaturated monoacylglycerols in the presence of micellar solutions of bile salts or caseins [5,23]. Later, Larsson and co-workers refined the dispersions of non-lamellar liquid crystalline lipid phases by using amphiphilic polymers as dispersants and these cubic phase particles were named cubosomes [5,14,15,24–26]. It should be noted that these dispersed particles are in equilibrium with water and retain their internal structure. Barauskas et al. demonstrated that the dispersion particle size and nanostructure can be controlled by varying the block copolymer concentration, the lipid composition and the salt content [27]. A range of different nanoparticle dispersions of self-assembled lipid mesophases with distinctive reversed bicontinuous cubic, hexagonal, sponge and reversed micellar cubic phase structures can thus be obtained (Fig. 2) [28–31]. Non-lamellar lipid LC nanoparticles (LCNPs) prepared by dispersing LC phases in the presence of a stabilizer are promising for several different administration routes, including intravenous injection, because due to their small size they may penetrate tissue or cells to deliver the drug to less accessible regions in our bodies [32–34]. Here, the ability of a LC phase or its nanoparticles to encapsulate a substance is known to be highly dependent on its degree of domain connectivity, since this determines the freedom of the enclosed molecules to diffuse within and out from the liquid crystals. Today, considerable effort is based on in vivo and in vitro studies of drug uptake, where the focus is on drug release from the vehicle as well as transport and absorption of the drug [35]. There are quite a number of reviews on the use of lipid liquid crystalline phases as drug delivery vehicles [15,17,18, 36–39]. Other than the ability to encapsulate drugs, the non-lamellar phase can also protect peptides from enzymatic digestion [15,36, 39–43]. The non-lamellar phases can be used for delivery through topical application to the skin, subcutaneous/intravenous injection and mucoadhesion, where the stickiness of the particle is an important factor [44]. However, less attention has been directed to the process at interfaces, although there is considerable research activity in the biomaterials section. For instance there is an increasing interest to achieve drug delivery from implant surfaces, e.g. elution of drugs from cardiovascular stents to prevent restenosis and the release of drugs from implants to prevent infection associated with orthopedic and dental implants [45].

water-in-oil L2

L1

I1 H2

H1

V1

Lα

I2

V2 L3

Fig. 1. Schematic illustration of different liquid crystalline phases. Reprinted with permission from [85]. Copyright 2008 Woodhead Publishing.

Please cite this article as: Chang DP, et al, Non-lamellar lipid liquid crystalline structures at interfaces, Adv Colloid Interface Sci (2014), http:// dx.doi.org/10.1016/j.cis.2014.11.003

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Fig. 2. Cryo-TEM images of different nonlamellar lipid liquid crystalline nanoparticles (LCNPs): reversed bicontinuous cubic phase (A–D), sponge or L3 phase (E–F) and reversed hexagonal phase (G–H) particles. Fourier transforms of magnified areas in panels b, d, f, and h show the structural periodicity of the different nanoparticles consistent with the mesophase structures indicated above. Reprinted with permission from [29]. Copyright 2005 American Chemical Society.

1.3. Lipid liquid crystalline phases deposited on surfaces The assembly of lamellar lipids at solid surfaces has been investigated extensively. The pathways of vesicle adsorption and bilayer formation have been elegantly studied using the QCM-D technique by Kasemo et al. [46–49] and Plunkett et al. [50]. Lipid bilayers are now routinely formed on surfaces with different properties, including polymer layers [51,52]. In addition they can be formed on surfaces with nano-features that generate lipid bilayers that are highly curved [53–55]. Interestingly, fluid supported bilayers deposited from vesicle dispersion can follow the contours of vertical nanowires even if they have a very high aspect ratio [53]. Proteins as well as vesicles could be attached to these highly curved bilayers. By changing the dimensions of the wires and their density one can create a curved bilayer that can be used to monitor biomolecular events like protein binding that in some cases may depend on the bilayer curvature. Another way to generate lipid layers with controllable curvature is to form tethered arrays of mobile vesicles on lipid bilayer. This strategy was pioneered by Boxer and his group at Stanford [56], and today this technique has been established to form 3D lamellar structures on a surface [57,58]. This review focuses on the third approach namely to utilize nonlamellar LCNPs for surface coatings. As for deposition from vesicular dispersions it is important to understand the nature of the interaction of the lipid crystalline structure with the interface. In fact the surface confinement can trigger the formation of non-lamellar surface films. We have previously shown that a cubic phase can be formed from a saturated glycerol monooleate (GMO) monomer solution within the confinement between two mica sheets, due to capillary induce phase separation [59]. The adsorption of lipid LCNPs, such as cubic or hexagonal phase nano-particles on the surface [60,61] can be achieved provided that there is sufficient driving force for the adsorption. By varying the supporting surface properties [62] and the LCNP lipid composition [63] we can also vary the surface excess and the structure. We will focus on recent progress in understanding the interfacial properties of LCNPs at the solid/liquid and biologically relevant interfaces such as biological

membrane and mucosa. The effect of surface chemistry, phase structure, and solvent conditions on the formation of non-lamellar lipid structures at the solid/liquid interface will be discussed. There is a fourth strategy that also will be discussed in this review, namely to deposit liquid lipid mixture from non-aqueous solutions using e.g. spin coating, followed by hydration in aqueous media [64]. 2. Solid–liquid interface 2.1. Adsorption of LCNPs at solid interfaces — effect of surface properties The adsorption of LCNPs can be used to form lipid based nonlamellar liquid crystalline surface layers and the structure formed depends on the strength of the surface interaction. Recent studies using null ellipsometry, QCM-D, AFM, florescence microscopy and neutron reflectometry of the adsorption of glycerol monooleate (GMO)based bicontinuous cubic phase nanoparticle (CPNP) stabilized by Pluronics F127, on hydrophobic and hydrophilic solid surfaces have revealed the effect of the surface properties [60,61]. The adsorption of LCNP on hydrophobic silica is dramatically different from that on bare silica [61]. On the hydrophobic surface, the hydrophobic attraction results in structural transition from the original particle morphology to a thin 3 nm monolayer coverage of lipid on surface (Fig. 3). One draw-back with the GMO-based LCNPs is that they have been shown to exhibit strong hemolytic activity especially at higher concentrations [65], which makes them less adequate as carriers for use in intravenous drug delivery. A mixture of soy phosphatidylcholine (SPC)/glycerol dioleate (GDO)-based LCNPs gives significantly better biocompatibility with a minimum of hemolytic properties [65]. Depending on lipid composition, e.g. SPC/GDO ratio, the nano-structure can be tuned from reversed micellar cubic (I2) and reversed hexagonal (H2) phases, in equilibrium with excess water [66,67]. These structures are readily dispersed into LCNPs by using an appropriate steric stabilizer such as polysorbate 80 (P80) [62,63]. Interestingly we also note that SPC/GDO/P80 LCNPs adsorbed rapidly at a hydrophobic silanized silica surface to reach a maximal adsorbed amount and layer thickness of 1 mg/m2

Please cite this article as: Chang DP, et al, Non-lamellar lipid liquid crystalline structures at interfaces, Adv Colloid Interface Sci (2014), http:// dx.doi.org/10.1016/j.cis.2014.11.003

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for SPC/GDO/P80 LCNP system, where we also note that this type of LCNP is only adsorbed in the presence of salt (0.1 M NaCl and 0.017 M CaCl2) or at a low pH (pH 4), while no significant adsorption could be detected in pure water (pH ≈ 5.5) (Fig. 4) [62]. Here it should be noted that both particles and silica surfaces are negatively charged at pH 5.5 and thus a net electrostatic repulsion is expected between the particles and the surface at higher pH values, i.e., pH N 5. If the surfaces are made cationic, either by chitosan coating or by silanization with 3aminopropyltriethoxysilane (APTES), the adsorption of LCNPs on both types of cationic surfaces is significantly larger than on bare silica surface. This further confirms that electrostatic attractive interaction can control the deposition of the LCNPs on surfaces. In addition we note that even if the chitosan coated surface promotes the attachment of the particles, the adsorption is fairly weak because of the relatively low cationic charge density obtained by chitosan adsorption. A more substantial increase of the cationic charge density can be achieved by chemically functionalizing the silica surface with a positively charged APTES. This leads to a substantial increase of the thickness and adsorbed amount of SPC/GDO/P80 LCNPs at the surface (Fig. 4). Fig. 3. Adsorbed amount (empty symbols) and layer thickness (filled symbols) as a function of time measured with ellipsometry after the addition of 0.05 mg/mL GMO-based LCNP in Milli-Q water (circles) and in the pH 2 water (triangles). Reprinted with permission from [61]. Copyright 2006 American Chemical Society.

and 1–2 nm, respectively, within a few minutes (Fig. 4) [62]. The adsorbed layer formation and properties on hydrophobic surface were basically independent of the initial particle size and consistent with what is expected for a lipid monolayer of SPC, GDO, or P80. On hydrophilic silica, thick layers of GMO lipid nanoparticles can be formed in the presence of electrolyte or at low pH [60]. Fig. 3 shows that the adsorption on hydrophilic silica is strongly dependent on the pH. At high pH, no adsorption is observed. At low pH close to the isoelectric point of silica, adsorption increases proportionally with time and reaches a saturation value at approximately 10 mg/m2. The layer thickness decays initially but stabilizes quickly and plateaus at around 40 nm. The adsorption curve suggests that the interfacial layer is built up by slow attachment of nanoparticles rather than of their molecular components. Consequently, the random lateral organization of bound nanoparticles visible from fluorescence microscopy and QCM-D demonstrates the large change in dissipation and a high stability of the viscoelastic particle at the interface [60]. The same trend is observed

2.2. Adsorption of LCNPs at solid interfaces — effect of particle composition and solution conditions The particle deposition is controlled not only by the surface properties, but also by molecular composition of the particles. Most notable is the role of particle steric stabilizer for the attachment of LCNPs. One can think of three different scenarios where (i) the stabilizer prevents adsorption, (ii) it makes the LCNPs more easily stick to the surface and (iii) free stabilizer competes for the surface binding sites. The later scenario is schematically illustrated in Fig. 5, where the interaction mechanisms of biocontinuous cubic LCNPs (known also as CPNP) with hydrophilic silica at different ionic strengths, particle size and pH are illustrated. Recently Tilley et al. studied quantitatively the interaction of F127 with GMO-based CPNPs and phytantriol (Phyt)-based CPNPs and hexagonal LCNPs (HPNPs) [68]. They found that the amount of free F127 (not attached to the LCNPs) as a function of concentration in the dispersions reached plateau values at a defined F127 concentration, i.e. at a defined critical aggregation concentration. Furthermore, the association of F127 with the LCNP appeared to be irreversible on dilution. Here it should be noted that the amount of bound stabilizer depends on the lipid composition as well as the nanostructure of the particle. As illustrated in Fig. 6, a larger amount of F127 was associated with Phyt/

Fig. 4. Adsorption of LCNP (GDO/SPC/P80) on silica surfaces with different surface chemistry and solvent conditions measured with ellipsometry. A shows the kinetics, while B shows the final adsorbed amount at steady state under different conditions. Adopted from Chang et al. [62].

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Fig. 5. Schematic illustration of factors that can control the adsorption of Cubosome LCNP (CPNP) stabilized with Pluronic F-127 molecule relative to the adsorption of small CPNP at a steady state on silica surface at pH 4 from 0.1 M NaCl aqueous solution (top): 1.) Removing salt increases repulsion between CPNP and surface and favors adsorption of stabilizer; 2.) Larger particles give less extensive adsorption, while 3.) increasing the pH to 6 with smaller particles, leads to a decreased adsorption of free F-127, and therefore an increased adsorption CPNP. Reprinted with permission from [60]. Copyright 2009 American Chemical Society.

vitamin E acetate (Vit EA) HCNPs than with Phyt CPNPs. The largest fraction of bound F127 was found for GMO-based CPNPs. It should be noted here that unit cell dimensions are larger for GMO-based than for Phyt-based CPNPs [69]. Yet another important aspect is the location of the stabilizer within CPNP as this can determine how much is accessible for the interaction between a particle and an interface. Based on surface area calculations and the F127 binding isotherm, Tilley et al. found that for the systems they studied (Fig. 6) F127 binds both to the internal and external surfaces of CPNPs.

Fig. 6. Quantification of F127 associated with different types of LCNPs, composed of different lipids, in dispersions containing 10.0% w/w lipid and 1.0% w/v F127. The binding is expressed as absolute concentration (left axis) and % of total F127 added on the right axis. Here the results from phytantriol, glycerol monooleate (GMO), phytantriol with 10% vitamin E acetate (Phyt:vitEA) and selachyl alcohol (SA) LCNP are shown. Data reproduced from Tilley et al. [68].

The role of steric stabilizers in anchoring, stabilizing and competing for adsorption sites has been demonstrated for various LCNP systems [60,63,70]. The effect of P80 on promoting adsorption is likely due to the known attractive and pH-sensitive interactions between the PEO segments of the P80 headgroup and the silica surface [61,62,71]. This is illustrated in Fig. 7, where increasing the P80 content of the GDO/ SPC particles increases the driving force for adsorption and consequently the adsorption onto the silica surface [62]. This can be related to the preferential location of P80 at particle surfaces discussed above. Other factors will also contribute to the observed effect, like the apparent decrease of the zeta potential of the LCNPs with increased P80 as well as the fact that flexible lamellar features of the surface of the LCNPs appear more extensive at 20 wt.% P80 than at 15 wt.% [62]. These lamellar features can facilitate adsorption and attachment of LCNPs at the surface by providing a larger contact area. The data in Fig. 7 also shows that SPC/GDO weight ratio also affects the adsorption. Here, the adsorption decreases with increasing SPC content, particularly at 20 wt.% P80. One reason could be that the SPC-rich particles are more hydrated as observed from the SAXD data and are therefore less densely packed at the interface. Another reason could be that the SPC rich particles, which are expected to be more hydrophilic as they contain less GDO, have less P80 on the surface and therefore a decreased driving force to attach onto the silica surface. Dong et al. [70] and later Tilley et al. [68] found less adsorption of F127 on Phyt CPNPs than those composed of Phyt/VitEA (90/10 wt/wt) which form HCNPs. This leads to less adsorption of mixed Phyt/VitEA LCNPs on hydrophobic surface than particles prepared from pure Phyt, which was ascribed to an increased repulsion between the F127 cover hydrophobic surface and the F127 coated particles [70]. The competition between the free stabilizer, e.g. F127, and GMO-based LCNP covered with stabilizer is also illustrated schematically in Fig. 5. Here one of the key features is that a small fraction of residual free polymer in the LCNP dispersions adsorb rapidly at the surface due to their smaller size

Please cite this article as: Chang DP, et al, Non-lamellar lipid liquid crystalline structures at interfaces, Adv Colloid Interface Sci (2014), http:// dx.doi.org/10.1016/j.cis.2014.11.003

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Fig. 7. Adsorbed amount (▼) and layer thickness (●) as a function of time after the addition of 0.1 mg/mL of SPC/GDO/P80 LCNPs on hydrophilic silicon surface in pH 4 water as recorded by in-situ null ellipsometry. The effects of P80 stabilizer concentrations as well as the composition of the particles are shown. The top row shows 15 wt.% P80 (A–C) and the bottom row 20 wt.% P80 (D–F). The SPC:GDO/P80 ratios were (A) 35:65/15, (B) 50:50/15, (C) 65:35/15, (D) 40:60/20, (E) 50:50/20, and (F) 60:40/20 and the total lipid concentration used was 0.1 mg/ml. The arrows indicate when rinsing with pure solvent occurred. Reprinted from Chang et al. [63].

and therefore compete for the adsorption sites. Hence, Vandoolaeghe et al. observed a lower steady state coverage for large LCNPs compared to that of small LCNPs as they adsorb intact to hydrophilic silica only in the gaps left between the randomly adsorbed polymer molecules, which due to steric repulsion hamper the adsorption of LCNPs [60]. We have also used neutron reflectometry and deuterated P80 to reveal the location of the stabilizer P80 within the adsorbed layer of SPC/GDO nanoparticles on an anionic silica and cationic APTES [72]. We noted that the P80 is located closest to the supporting surface and slightly more so for the cationic APTES surface. Here it should be added that P80 on its own at the same concentration as in the LCNP dispersion also readily adsorbs to both the silica and the APTES surface [73] . The NR data obtained for P80 adsorption could be fitted to a layer of P80 micelles. 2.3. LCNP interactions with models of biological interfaces The uptake of LCNPs through the skin, mucosa or the cell membrane is crucial to their use as drug delivery vehicles and involves interaction with biointerfaces. Another aspect of importance is to limit the hemolytic activity of the LCNP as drug delivery vehicles. The development of drug delivery vehicles also concerns their stability in formulations. This means that the vehicles should be in a stable dispersion and the loss of material in terms of adsorption to vials, catheters, tubes and other delivery devices should be minimal. LCNPs might also be disintegrated by contact with an interface, for instance as happens with the GMO-based CPNPs on the hydrophobic surface discussed above. There are also instances where a maximum possible adsorption is desirable, such as when the LCNPs are used as surface coatings and for enhancing drug delivery. To date, only a few but increasing number of studies have aimed to reveal the mechanism of the interfacial interaction between LCNP with the type of surfaces in which they will encounter. Supported lipid membrane models have been used to model the interaction between LCNP and the cell membrane, where surface sensitive

techniques, like ellipsometry, QCM-D, and NR can provide insight into the interaction mechanism as well as revealing the kinetically controlling processes [74,75]. The rapid increase in the adsorbed amount observed after the introduction of GMO-based LCNP to a supported dioleoyl phosphatidylcholine (DOPC) bilayer on silica suggests a strong attraction between the particle and the bilayer. The adsorbed amount peaks and decreases after about an hour, signifying a net release of material from the surface. The QCM-D measurement shows that after addition of LCNP, the surface becomes viscoelastic with a large change in dissipation. The wet mass measured through viscoelastic modeling of the surface layer indicates an initial adsorption of intact nanoparticles followed by relaxation and release. NR measurements were used to monitor the composition of the initially deuterated phospholipid bilayers versus time after LCNP addition. The neutron data showed that a significant lipid exchange between the nanoparticles comprised of hydrogenated GMO and the deuterated DOPC bilayer [75]. The exchange takes place regardless of the initial bilayer coverage [74]. The rearrangement within the surface layer results in interfacial instability that releases particles after a critical amount of lipids have been exchanged. Complementary SAXD study of the interaction between unilamellar DOPC vesicles and the CPNP particles revealed that an additional lamellar phase appears with time, which demonstrated that the lipid exchange between CPNPs and vesicles leads to local phase change that could be related to the phase diagram of the bulk system [69]. In addition, the cubic phase unit cell dimension decreases with time and the peaks corresponding to the cubic phase eventually disappear. The exchange between the CPNP and the supported lipid bilayer is slower, when the bilayer was made up of lipids in the gel state, e.g. dipalmitoyl phosphatidylcholine (DPPC) [69]. The interesting and controllable interaction of the nanoparticles with model membranes, where the particles release are triggered by a local phase transition due to the lipid exchange, demonstrates an interesting concept for the phase change triggered release that might have potential in drug delivery systems. LCNPs can also be modified to target specific membrane components. This was demonstrated by Shen et al. who studied the interaction

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of Annexin V (ANX) decorated phosphatidylserine (PS) containing Phyt cubosomes with apoptotic model and cellular membranes [76]. The apoptotic model membrane was prepared from a palmitoleoyl phosphatidylcholine (POPC)/palmitoleoyl phosphatidylserine (POPS) (2:1, wt/wt) mixutre. Both QCM-D and NR showed strong binding of ANX-PS/Phyt CPNPs to a model apoptotic membrane. Consistent with our findings described above, they also observed changes in both the bilayer structure and in the internal structure of the CPNPs in a region adjacent to the membrane. This was also attributed to material exchange upon attachment of the particle to the model membrane. The mucous membrane is the outermost lining layer of many biological systems, for example, the mouth, stomach walls, intestines, eyes, and genital areas. A prerequisite for applying LCNP in oral and topical delivery systems is to understand the interaction between the mucous gel layer and lipid LC phases. In an early work, the mucoadhesion property of GMO was tested using a flow system with an exposed intestinal surface where GMOcoated solid particles form liquid crystals once in contact with the wet mucosa [77]. Later, the interaction between LCNP and mucin, the main constituent of the mucous layer, was investigated using nullellipsometry and particle electrophoresis [71]. This work showed that there is a weak attraction between the particles and mucin that is rather similar to the interaction between mucin and PEO chains. This finding suggests that the PEO chains from F127 stabilizer on CPNP surface control the adsorption behavior. Furthermore, to enhance the interaction between particle and the mucin surface, GMO-based LCNPs were modified with positively charged chitosan [78]. The chitosan-modified LCNPs show substantially larger adsorption on a mucin surface compared to the unmodified particles. The result suggests that the electrostatic attraction between the positively charged chitosan and negatively charged mucin increased the adsorption. This study demonstrates the potential of chitosanmodified LCNP for mucosal drug delivery applications and reconfirms that surface-modification of LCNP can be tailored to promote surface adhesion. It is thus clear that the composition of LCNP can be used to tune the bioadhesive properties of the formulation. This has recently been demonstrated by Barauskas et al. [44], who were able to relate the self-assembly properties of phosphatidylcholine (PC) and glycerol dioleate (GDO) mixtures in the presence of aqueous fluids to functional attributes of the system. This included film formation and bioadhesion, intraoral coverage, acceptance by patients, and potential as a drug delivery system. They found the optimum in functional properties for formulations with a PC/GDO weight ratio of about 35/65, where the lipids form a reversed cubic liquid crystalline micellar phase structure (Fd3m space group) over the physiologically relevant temperature range (25–40°°C). Inspired by the enhanced delivery of pharmaceutically active ingredients using LCNP, Dong et al. [79] have examined the possibility of using LCNPs to deliver active molecules to hydrophobic plant leaf surfaces. They used ATR-FTIR to monitor the adsorption of cubic and hexagonal LCNPs on model and real leaf surfaces (Fig. 8). Their study also shows that the adsorption behavior is dependent on the internal nanostructure with higher adsorption and delivery efficacy for the cubic phase particles than the hexagonal counterpart. The difference in adsorption is explained by the difference in free energy gained due to structural changes during attachment to the surface [79]. The hexagonal LCNPs show faster adsorption kinetic and larger free energy gain upon particle adsorption, which could be related to the release of internal stress from the unfavorable internal packing geometry. Therefore these LCNPs spread more easily than the cubic ones, which leads to higher coverage but also to lower total amounts adsorbed. These findings are also consistent with the high viscosity of liquid crystalline cubic phases compared to the hexagonal phase [5]. The adhesion strength of the nanoparticles to biologically relevant surfaces was found to be dependent on the lipid system [79]. GMObased LCNP showed weaker surface adhesion compared to the Phyt-

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Fig. 8. ATR-FTIR spectra of cubosome and hexosome coated model leaf surfaces after 100 min of adsorption. Reprinted with permission from [79]. Copyright 2011 American Chemical Society.

based LCNP even though the same stabilizer, Pluronic F127 was used for both types of particles. The difference in the adhesion strength was proposed to be dependent on the different interaction between F127 stabilizer and the lipid LC structure. As discussed above, when providing steric stabilization the stabilizer can be located at both the external and internal surfaces of the LCNP [79,80]. It has been proposed that a strong interdigitation between F127 and GMO-based LCNP inhibits strong particle adsorption and results in weak particle surface adhesion on certain surfaces. On the other hand, Pluronic F127 loosely adheres on the surface of Phyt-based LCNPs, which can decrease the particle stability and consequently lead to increased surface deposition. The Phyt-based LCNP has been shown to withstand extensive agitation that might be relevant for agriculture applications where mechanical resistance is desirable. 3. Structural characteristics 3.1. Organization of the adsorbed layer Monitoring the lateral organization of the adsorbed LCNP layer can be challenging as the particle size is below the resolution of an optical microscope. One of the first studies of adsorption of GMO-based LCNPs on solid surface was actually published already 1999. Neto et al. here used AFM to monitor the particles and their results suggested that a slight height deformation occurs upon adsorption [81]. However, by using a fluorescent dye and fluorescence microscopy an image of the lateral organization can also be obtained. This is illustrated in Fig. 9, where the attachment of GMO-based LCNPs is shown versus time [60]. Further information on the extension of the adsorbed layer as well as structural transition that can occur can be revealed by QCM-D. In

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Fig. 9. Fluorescence microscopy images recorded with a 63× objective during the adsorption of 0.01 mg mL−1 large GMO-based LCNPs adsorbed from 0.1 M NaCl at pH 4 to hydrophilic silica after incubation times of (A) 0.5, (B) 1.3, (C) 2.3, and (D) 4.5 h. The white scale bar corresponds to a length of 20 μm. The insets are magnifications of the corresponding images, each with an area of 17.3 μm × 10.1 μm. The data reproduced from Vanoolaeghe et al. [60].

addition to being sensitive to the total mass on the surface, this acoustic technique can monitor the change in viscoelastic properties of the layer as well as coupled water [57,82]. This is illustrated in Fig. 10 where the adsorption of LCNP is compared to that of the phospholipid-based lamellar vesicles on hydrophilic silica interfaces [60]. The lamellar vesicles adsorb intact on hydrophilic surface at low coverage, and transform into a bilayer arrangement after a critical coverage [46,47]. The collapse of the surface-attached vesicles is shown as a kink in the correlation plot

of dissipation change, ΔD, as a function of frequency shift, Δf, as seen with the solid line in Fig. 10. The drop in dissipation signifies the disruption and spreading of the vesicle and release of solvent mass. For the adsorption of LCNPs, a monotonic increase of ΔD versus Δf with no kink shows that the bound particles remain largely intact with significant amount of acoustically coupled water. The schematic drawings in Fig. 10 illustrate the different adsorption behavior of non-lamellar crystalline particle and lamellar vesicles on the hydrophilic silica surface. It should be noted here that QCM-D is very sensitive to probe the attachment of LCNPs that protrude from the surface into the bulk solution. In fact with QCM-D one can detect extended layers of LCNPs of low density, when techniques like NR, ellipsometry and X-ray reflectometry are not able to unambiguously determine the particles at larger distances from the solid/liquid interface [31,73]. 3.2. The internal structure of the layer

Fig. 10. QCM-D correlation plot of dissipation difference, ΔD, as a function of frequency shift, Δf, for the adsorption of small (○) and large (●) cubosomes on hydrophilic silica surfaces. The solid line represents the adsorption and fusion of vesicles on silica surface. Reprinted with permission from [60]. Copyright 2009 American Chemical Society. Schematic drawings illustrate the intact crystalline nanoparticles after adsorption (left) and lipid bilayer formed from vesicle fusion (right).

One important question for potential applications is whether and to what extent is the internal liquid crystalline structure of the LCNP conserved when the particles adsorb to the surface. Specular reflection techniques probe the structure orthogonal to the surface so any repeating structure will appear as a Bragg diffraction peak. One example of such system, is the adsorption of GMO-based particles on the silica surface, for which the NR data are shown in Fig. 11. The data features a Bragg diffraction peak to which a multilayer model can be fitted [60]. These results indicate that intact LCNPs attach to hydrophilic surfaces without significant structural changes and spreading, as monitored for over 40 h. It is also noteworthy that the Bragg peak increases with time until steady state is reached indicating the particle density on the surface increasing with time, which is consistent with the fluorescence microscope image in Fig. 9. At steady state the curves fit very nicely to the cubic phase model with a repeating distance of 5.2 nm representing

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Fig. 11. Neutron reflectivity, R, as a function of momentum transfer, Q, recorded for adsorption of GMO-based LCNPs on hydrophilic silica (A) in 0.1 M NaCl at pH 4.4 in D2O at different incubation times and (B) in D2O (filled squares) and cmSi (open triangles) at 45 h time. The solid lines (B) correspond to the modeled fits to the data using the cubic phase model. A shows a schematic drawing, where scattering density profile is modeled as a sinusoid used for the fit. Reprinted with permission from [60]. Copyright 2009 American Chemical Society.

the cubic LC phase organization at the surface [32]. It should also be noted that a model fitted to the reflectivity profile has to include a layer adjacent to the surface with significantly more material than the adjoining layer with a repeating structure (intact LCNPs). These layers are established directly after the LCNP dispersion and do not directly correlate with the architecture of the LCNPs layer. This result suggests that there is a competing interfacial process to the adsorption of intact LCNPs. Such a process involves the formation of a layer, which is likely to be composed of free polymers as discussed above. We also note that this layer adjacent to the surface also occurs in the SPC/GDO/P80based particles, where the layer composition is influenced by the surface characteristics [72,73]. We have recently investigated the effect of stabilizer on SPC/GDO (50/50 wt/wt) LCNPs prepared at different fractions (5–15 wt.%) of the P80, using SANS and SAXD [72]. This study showed that the P80 concentration should be kept as low as possible to avoid stabilizer-related structural disordering effects on the particles and minimize the fractions of coexisting mixed surfactant/lipid micelles in the dispersions. Yet at the same time the concentration should be high enough to stabilize dispersions of the LC phase. A concentration of 5 wt.% P80 was found to be sufficient to disperse the bulk SPC/GDO LC phase and SANS data suggests that already at this low concentration some P80 penetrates the particle core. However, the fraction of P80 solubilized in the interior of the particles is still low enough not to significantly interfere with the internal Fd3m cubic structure of the nanoparticles. At higher fractions of P80 a phase separation occurs, in which a SPC and P80 rich phase is formed at the particle surface, previously depicted by cryo-TEM for SPC/GDO nanoparticles and by SAXD for bulk LC phases at high fractions (15–20 wt.%) of P80 [31,62,63]. The surface layer becomes gradually richer in both solvent and P80 when the concentration is increased, while the core of the particle is enriched by GDO, resulting in loss of ordered micellar cubic internal structure and reduced hydration.

Thin films of non-lamellar reversed lipid LC phases with controllable thickness of few micrometer can be formed on solid surfaces [64]. For this purpose non-aqueous SPC/GDO (35/65 wt/wt) formulation in ethanol was spin-coated on solid surfaces. This resulted in Fd3m LC films which were 0.5 and 5.6 μm thick after hydration in aqueous solution, as measured by spectroscopic ellipsometry (Fig. 12). The Fd3m nanostructure of the film was verified by diffraction patterns obtained from synchrotron SAXD on films deposited on mica. Such lipid films are only 30–360 repetitive units thick and may thus allow for studies of lipid adhesion to surfaces and which effects the surface confinement has on the LC phase. This is key knowledge in the development of topical drug delivery systems, in which the lipid LC phases are designed to adhere to different biological surfaces. As mentioned previously, the exchange of lipids can take place when e.g. GMO-based LCNP interacts with the supported phospholipid bilayer. The amount of lipid exchange can be quantified with NR by determining the composition of hydrogenous components of LCNP (GMO and F127) and the deuterated bilayer (d-DOPC). The results show that the final composition of the lipid layer on surface at the end of an exchange depends very much on the initial bilayer coverage [74]. At high bilayer coverage, the addition of CPNP leads to an extensive exchange of lipids. The final bilayer is composed of about 72% of the CPNP components and the surface contains very little residual intact particles. At lower bilayer coverage, spreading of LCNP components fills in the defects of the bilayer. At the same time, a substantial adsorption of the intact particles can be seen by the presence of the Bragg diffraction peak [74]. The lipid exchange can also change the composition of the adsorbed LCNP and induce a phase change of the particle. NR data show the incorporation of d-DOPC molecules from the bilayer into the GMO-based CPNP [74]. The incorporation of DOPC shifts the composition from the cubic phase toward the mixture of cubic and lamellar phase and

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Fig. 12. (A) Spectroscopic ellipsometry data (Ψ (filled circles) and Δ (open circles)) of a 35/65 wt.%/wt.% SPC/GDO film in water. The non-aqueous lipid film was spun for 20 s at 8000 rpm and the model fit (lines) revealed a thickness of 5.6 mm. (B) SAXD data of the 35/65 wt.%/wt.% SPC/GDO film in H2O at 25 °C. The index corresponding to the face-centered cubic micellar phase is indicated. Data extract from Wadsäter et al., 2013 [64].

possibly pure lamellar phase. This conclusion can be derived from the equilibrium GMO/DOPC/D2O phase diagram. Such a transition can lead to a contraction of unit cell dimension of the cubic structure, and shifts the Bragg diffraction peak toward higher momentum transfer, Q, values. The shift and broadening of the Bragg diffraction peak are observed over time, which are consistent with the progression of the lipid structure toward a new phase from the incorporation of d-DOPC from the bilayer into the GMO-based particle. This demonstrates that a phase transformation of LCNP can occur when an interfacial interaction alters the composition of the LC particles. NR data has also shown that there is a strong interaction and material exchange between the ANX-PS/Phyt particles and the POPC/POPS model of an apoptotic lipid bilayer [76]. Cryo-TEM was used to visualize the intermediate states of the dispersions resulting from material exchange processes when mixing of ANX-PS/Phyt CPNPs and POPS/ POPC vesicles at a ratio of 1:1. The obtained images show fusion and presumably mixing between POPC/POPS vesicles and CPNPs is consistent with the NR data. A similar behavior was observed from synchrotron SAXD studies of pure Phyt-based CPNPs interacting with POPC

vesicles [83]. The migration of POPC from the vesicles into the cubic phase lattice was here observed from variation in the location and intensity of the Bragg reflections, which in turn lead to swelling of the internal nanostructure and a reduction in long-range LC order. 4. Applications and future outlook To use the LCNP as a delivery agent, it is important to understand its physical properties and interactions with the encapsulated molecules. Furthermore, it is crucial to understand the interfacial property between LCNP and the surface where the particles will interact. For drug delivery purpose, there is a need to develop new lipid compositions with low physiological toxicity. Systematic studies, as developed in some of the works cited, to monitor the interaction of the nanoparticles with model membranes can then be related to the synthesis of new formulations to assess their potential for delivery applications. LCNP can also be used to prepare LC surface films with well-defined nano-structures. These surface films can be formed through simple adsorption of the nanoparticles, direct deposition of the LCNP precursors, and also built

Fig. 13. A spherical silica particle is used as a template for forming polymer capsules containing cubosomes. The polymer layers are formed via layer-by-layer deposition using two oppositely charged polymers, PSS and PAH. First the silica particle is coated with a number of precursor polyelectrolyte layers after which the Cubosomes are adsorbed. Finally, five capping layers of polyelectrolyte are added to entrap the cubosomes between polymer layers prior to the removal of the silica core. From Driever et al. [84] Reproduced by permission of The Royal Society of Chemistry.

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Fig. 14. Cryo-TEM images of 50/50 SPC/GDO nanoparticles in 0.12 M Tris and pH 7.5 degraded by TGL at 37 °C. The sequential evaluation of phases is illustrated. From Wadsäter et al. [31].

up from the lipid components. The LC structure on surfaces can be altered because phase transitions can take place upon adsorption. The inclusion of guest molecules can also change the LC structure and the manner of interaction with the surfaces. Thus, the surface structure will need to be systematically monitored, as described previously, to ensure that a well defined crystalline structure is maintained. Even after depositing a layer of LCNP there is a need to further modify and potentially also protect the layer. This is elegantly demonstrated by Driever et al. [84]. They prepared microcapsules by the layer-by-layer (LbL) polyelectrolyte adsorption technique that contained embedded CPNP into the capsule shell wall. A schematic sketch of their approach is shown in Fig. 13. They used a multilayer assembly of oppositely charged polyelectrolytes [poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS)] first tested on planar silica substrates. Then the observed build-up was correlated to the multilayer build-up that incorporated CPNPs onto silica microparticles, as verified by z-potential measurements and SAXD measurements to verify that the deposited CPNP nano-structure remained intact during the process. The silica core could then be removed, resulting in stable microcapsules containing one layer of embedded cubic nanoparticles. Another way to manipulate the particles is to expose them to change of conditions, e.g. by the action of lipolytic enzyme, temperature or by deposition on structured substrates. As first observed by Patton and Carey [22], the digestion of dietary fat (triglycerides) catalyzed by pancreatic lipases leads to the formation of different lipid LC phases. Since then several studies on the LC phase and colloidal transformations during the digestion of lipid assemblies, emulsions of acylglycerides or LCNPs of containing polar lipid have been presented [31,85–90]. These have shown that apart from the lipid composition and the type of lipolytic enzyme, the solution conditions like bile salt concentration, pH (i.e., the degree of protonation of the fatty acids), and buffer conditions are important both for the kinetics of the lipolysis and the formed LC nanostructure. For instance Salenting et al. showed that highly ordered nanostructures are formed during the digestion of milk fat globules catalyzed by lipolytic enzymes as observed by time-resolved synchrotron SAXD and cryo-TEM [88]. They observed that at low-bile conditions highly ordered lipid particles with substantial internal surface area are formed. Recently we showed how the structure of the GDO/SPC LCNPs, discussed above, evolves structurally during the exposure to a triacylglycerol lipase (TGL) under physiological-like temperature and pH (Fig. 14) [31]. Here it should be noted that TGL catalyzes the lipolytic degradation of one of the lipid components, namely GDO, to monoglycerides, glycerol, and free fatty acids. During the degradation, the LC structure of the interior of the particles changes continuously from the reversed Fd3m structure to structures of less negative curvature (2D hexagonal, bicontinuous cubic, and sponge) and finally results in the formation of multilamellar liposomes. An interesting way to make lipid-based LC matrixes stimuliresponsive by an external stimuli was presented by Fong et al. [91]. By including gold nano-rods in the lipid LC phases and shining light to

heat the sample one could induce a phase transition on demand. The phase transition is reversible by switching off the laser. Lipid based self-assembled particles do not only consist of simple bilayer structures. Today non-lamellar lipid assemblies have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Inspired by biology the researchers today strive to develop simple non-lamellar bio-mimicking systems with potential applications in biomedical devices for analyses and drug delivery. This also provides fundamental knowledge that can be of relevance for understanding of the much more complex phenomena in biological systems. Here we have discussed how knowledge of structural changes of deposited lipid in relation to the corresponding bulk dispersions can be used to control biointerfaces. This can be achieved by changing the lipid composition or by introducing components that can alter the curvature. Also changes in the supporting surface topology as well as those invoked by enzymatic activity can be used to modify the interfacial lipid layer structure. The generated knowledge of non-lamellar lipid liquid crystalline structures at interfaces will provide new leads for controlled delivery in food, cosmetics, consumer products and pharmaceuticals as well as novel bioanalytical systems. Acknowledgments We would like to dedicate this paper to Prof. Reinhard Miller for promoting surface and colloid science through many years and keeping this community together. We are also grateful to all our colleagues for many stimulating discussions on lipid liquid crystalline nanoparticles and interfaces. Financial support was obtained from the Swedish Foundation for Strategic Research (RMA08-0056) as well as the Swedish Research Council (2010-5015). References [1] Evans DF, Wennerström H. The colloidal domain : where physics, chemistry, biology, and technology meet. 2nd ed. New York; Chichester: Wiley-VCH; 1999. [2] Mouritsen OG. Life – As Matter of Fat. The emerging Science of Lipidomics. Heidelberg: Springer-Verlag; 2005. [3] Seddon JM. Structure of the inverted hexagonal (HII) phase, and non-lamellar phase transitions of lipids. Biochim Biophys Acta 1990;1031:1–69. [4] Luzzati V. X-ray diffraction studies of lipid-water systems. In: Chapman D, editor. Biological Membranes. New York: Academic Press; 1968. p. 71–123. [5] Larsson K. Cubic Lipid-Water Phases — Structures and Biomembrane Aspects. J Phys Chem-Us 1989;93:7304–14. [6] Fontell K. X-ray diffraction by liquid crystals & amphiphilic systems'. In: Gray GW, Winsor PA, editors. Liquid Crystals and Plastic Crystals, Chichester, Ellis Horwood. Chichester: Ellis Horwood; 1974. p. 80–109. [7] Powell GL, Marsh D. Polymorphic behavior of cardiolipin derivates studied by 31PNMR and X-ray diffraction. Biochemistry 1985;24:2902–8. [8] Furse S, Brooks NJ, Seddon AM, Woscholski R, Templer RH, Tate EW, et al. Lipid membrane curvature induced by distearoyl phosphatidylinositol 4-phosphate. Soft Matter 2012;8:3090–3. [9] Mulet X, Templer RH, Woscholski R, Ces O. Evidence That Phosphatidylinositol Promotes Curved Membrane Interfaces. Langmuir 2008;24:8443–7.

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Please cite this article as: Chang DP, et al, Non-lamellar lipid liquid crystalline structures at interfaces, Adv Colloid Interface Sci (2014), http:// dx.doi.org/10.1016/j.cis.2014.11.003