Design of Light-Triggered Lyotropic Liquid Crystal Mesophases and

Article pubs.acs.org/Langmuir

Design of Light-Triggered Lyotropic Liquid Crystal Mesophases and Their Application as Molecular Switches in “On Demand” Release Simone Aleandri,† Chiara Speziale,‡ Raffaele Mezzenga,‡ and Ehud M. Landau*,† †

Department of Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland Department of Health Science and Technology, ETH Zürich, Schmelzbergstrasse 9, LFO, E23 CH-8092 Zürich, Switzerland

‡

S Supporting Information *

ABSTRACT: Here, we present the design and assembly of a new light-responsive functional lyotropic liquid crystal system using host−guest lipidic mesophases (LMPs). Light as an external stimulus has many advantages in comparison to other stimuli: it is milder than acids or bases, and variation of intensity and duration can provide a high level of pharmacological control. The LMPs are composed of monoolein (MO) and oleic acid (OA) as host lipids and a small amount of a judiciously synthesized lipid bearing an azobenzene photoactive unit as a guest. While preserving the structure and stability of the host lipidic aggregates, the guest lipids render them specific functionalities. Single-step and sequential light-triggered release and retention of the embedded dye molecules are demonstrated, thereby achieving exquisite temporal, spatial, and dosage control of the release, opening up the possibility of using such lipidic biomaterials as effective matrices in therapy, when a continuous release of active drugs might be toxic.

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INTRODUCTION Nanocarriers offer many advantages in drug delivery compared to conventional formulation methods.1 They protect the drugs upon administration, enhance their in vivo efficiency by delivering the therapeutic agent to the required sites, and prevent side effects.2 Moreover, with appropriate molecular design, it is possible to trigger drug release to achieve temporal and spatial control of the delivery of therapeutic agents, thereby achieving a higher local concentration. This is an advantage when continuous release of active ingredients might be toxic, and an “on/off” switching should provide control over effectiveness of the therapy.3 In the field of controlled release, it is possible to obtain drug release in response to various internal and external triggers, such as pH,4 temperature,3 ultrasound,5 and light.6,7 Among the external stimuli, light has many advantages,8 because it can be remotely applied with extremely high spatial and temporal precision. Moreover, the wavelength, light intensity, duration of exposure, and spot size can be exquisitely controlled9,10 to modulate release profiles and provide a high level of pharmacological control.11,12 Light can directly affect the assembly of the nanocarrier, which leads to release of the encapsulated bioactive agent.13 A number of molecular classes are known to undergo photoisomerization. Azobenzenes, possessing a −NN− moiety with phenyl rings on both sides, are of the most commonly used molecules for this purpose, and their photoisomerization is a well-defined and extensively applied process.14 The planar, more stable trans configuration is more hydrophobic than the nonplanar cis © 2015 American Chemical Society

configuration. Azobenzenes are attractive in applications that require delivery on demand because their isomerization is reversible; the trans-to-cis isomerization is induced by ultraviolet (UV) irradiation, while the reverse cis-to-trans photoswitching can be accomplished using blue light (460 nm). Thus, azobenzene amphiphiles have been used to modify various self-assembled systems, such as microemulsions, organogels, and vesicles.15−17 UV-responsive chemical moieties can be used for topical treatments and in ophthalmology.18 Responsive drug delivery systems include liposomes, micelles, dendrimers, and polymer and inorganic nanoparticles. Despite substantial scientific and technological advances, a number of problems still persist, including toxicity, biocompatibility, biodegradability and efficiency of targeting. Synthetic polymeric systems often exhibit toxicity issues; biocompatibility and biodegradability are practical problems that are often encountered with inorganic nanoparticles; and, significantly, in most drug targeting systems, less than ∼5% of the active compound reaches the diseased site.11 An ideal drug delivery system should be biodegradable and biocompatible, incorporate the active agent without loss or alteration of its activity, and provide an efficient and controlled delivery mechanism to the specific location in vivo.19 Lipidic mesophases (LMPs) constitute alternative delivery systems that can be triggered by external stimuli.7,20 One of the most commonly used lipids for the formation of LMPs is monoolein (MO), which exhibits Received: April 12, 2015 Published: June 3, 2015 6981

DOI: 10.1021/acs.langmuir.5b01945 Langmuir 2015, 31, 6981−6987

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Figure 1. Structures of the synthetic guest lipid 1 and the host lipids MO and OA. and dye-loaded mesophases, respectively. The final MG concentration in the LCPs was 0.1 mM. To obtain homogeneous and viscous LMPs, samples were centrifuged in a fixed-angle Eppendorf desktop centrifuge (at 13 200 rpm) for at least 1 h at 37 °C. Samples were finally stored and left to equilibrate for 1 week in tightly closed vials at 37 °C in the dark. The final lipid and aqueous solution contents were 60 and 40% (w/w), respectively, for the LCPs and 70 and 30% (w/w), respectively, for the HII phases. Small-Angle X-ray Scattering (SAXS). SAXS measurements were used to determine the phase identity and symmetry of the LMPs used in the release experiments. A microfocused Rigaku X-ray source of wavelength λ = 1.54 Å was used, operating at 45 kV and 88 mA. Diffracted X-ray signals were collected on a gas-filled two-dimensional detector. The scattering vector q = (4π/λ)sin θ (with 2θ being the scattering angle) was calibrated using silver behenate. The sample− detector distance was 1 m, which provided a q range from 0.01 to 0.5 Å−1. Data were collected and azimuthally averaged using the Saxsgui software to yield one-dimensional intensity versus scattering vector q. Samples were loaded in a Linkam hot stage between two thin mica sheets and sealed with an O-ring, whereby the sample thickness was ca. 1 mm. Samples were equilibrated at 37 °C for 10 min prior to measurements, and scattered intensity was collected for 1 h at 37 °C. A mathematical model was used to calculate the structural parameter of the HII phases. Briefly, following determination of the lattice parameter by SAXS and assuming that the fixed lipid volume fraction, ϕ, and the HII geometry of the system remain constant, the radius of aqueous channels (r) and the length of lipid chains (Llip) can be calculated according to Mezzenga et al.32 Release Experiments. Specially designed, homemade stainlesssteel holders with outer dimensions that fit in a spectroscopic cuvette,33 the top of which containing a disc-shaped cavity, which can be filled with LMPs, were used for the release experiments. The surface of the LMPs was shaped with a spatula, thereby achieving a well-defined and controlled geometry and a constant and reproducible surface area/volume ratio. In the release experiments, the holder containing LMPs (100 mg) was placed in a spectroscopic cuvette and the LMPs were overlaid with PBS (at pH 7.4). A total of 1 mL of the solution overlaying the mesophases was removed periodically for spectroscopic determination of the concentration of dye released and replaced with the same volume of fresh solution to simulate perfect sink conditions.4 All experiments were carried out at the physiological temperature of 37 °C. The concentration of the molecules released from the aqueous compartments of the LMPs into the overlay was evaluated by absorbance spectroscopy after exposure of LMPs to light. The percentage of the dye released into the overlay was calculated from eq 1 and plotted versus the square root of the time

one-, two-, and three-dimensional self-assembled mesophases in the presence of water, corresponding to the hexagonal (H), lamellar (L), and lipidic cubic phases (LCPs).21,22 The hexagonal phase consists of an ensemble of micellar cylinders packed into a hexagonal lattice. Hexagonal phases can be either “normal” (HI), with a positive curvature toward the hydrocarbon chain region of the lipid, or “inverse” (HII), displaying a negative mean curvature toward the aqueous interior. The lamellar phase consists of a two-dimensional stack of amphiphilic bilayers separated by aqueous layers.23 Each bilayer consists of two monolayers arranged in a head-to-head and tail-to-tail packing to minimize the contact of the hydrocarbon chains with water. LCPs are composed of bilayers that are curved in three-dimensional space such that every point on their surface is a saddle point with a zero mean curvature. These structured yet flexible sponge-like bilayers encompass a system of aqueous channels, forming non-birefringent and optically transparent phases.21 LCPs and HII are the most interesting lipidic mesophases in the field of drug delivery.24,25 Both nanocompartmentalized biomaterials are thermodynamically stable26 and nontoxic.27 The compartmentalization of the LMPs can be used to introduce either hydrophilic, lipophilic, or amphiphilic molecules,28 thus rendering LMPs ideal molecular carriers.29 Because their surface properties can be tuned from hydrophilic to lipophilic, they can, in principle, be applied to any specific location in vivo, thereby achieving exquisite spatial control, which, in combination with the designed lighttriggering mechanism, can enable unprecedented temporal and dosage control of drug delivery. Here, we present a host−guest system composed of a mixture of MO and oleic acid (OA) as the host lipids and the designer synthetic lipid 1 as the guest, in which the photoactive azobenzene unit is linked via an ether bond at the end of the alkyl tail of MO (Figure 1). The addition of small amounts of the designer guest lipid 1 results in modified, light-responsive functional LMPs that exhibit triggered release behavior. Conditions are established for single-step and sequential light-triggered release and retention of an embedded hydrophilic dye, the cationic methylene green zinc chloride double salt (MG), upon irradiation with UV and visible light, respectively.

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EXPERIMENTAL SECTION

percent release = (A t / A tot ) × 100

Chemicals and Reagents. 1-Monooleoyl-sn-glycerol C18:1 (MO) and OA was purchased from Nu-Chek Prep, Inc. (Waterville, MN). MG was purchased from Fluka, and phosphate-buffered saline (PBS (1×), pH 7.4) was purchased from Invitrogen. All solutions were prepared using Mill-Q water (18.2 MΩ cm−1; Millipore, Bedford, MA). Lipid 1 was synthesized and described in an earlier publication from our laboratory.30 Preparation of LMPs. The ratio of components was chosen on the basis of the published phase diagram for the MO/water and MO/ OA/water systems.26,31 Briefly, MO was melted (at 42 °C), cooled to room temperature while remaining in the liquid state (undercooled), and mixed with OA and lipid 1 in a bench shaker (Grant Bio). The mixture was subsequently hydrated by adding appropriate volumes of PBS solutions at pH 7.4 without and with MG to prepare the empty

(1)

where At is the absorbance of the dye that is present in the overlay at time t during the release experiment and Atot is the absorbance of the dye in overlay after 100% release.

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RESULTS AND DISCUSSION Phase Identity. To evaluate the influence of the guest lipid on the phase identity and unit cell size of the host−guest system, mesophases were prepared and analyzed with SAXS. SAXS experiments were performed on the formulation doped with guest lipids under identical conditions to those implemented in the triggered release experiments (see below). In the SAXS regime, sharp Bragg reflections character6982

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Negrini et al. have demonstrated that drug release from a Pn3m cubic phase is ca. 4 times faster than that from a hexagonal phase (HII).4 Hexagonal phases that are able to more effectively retain the dye were therefore prepared. OA was embedded at a level of 14% (w/w) in the mesophases, and SAXS experiments were carried out on empty mesophases and on formulations that contain the dye (MG, 0.1 mM). These measurements (summarized in Table 2) demonstrate that functionalization of the mesophases by the addition of the guest lipid 1 and presence of the positively charged dye MG at the levels used do not affect the phase identity and unit cell size of the MO/OA/H2O system (the percentage (w/w) of MO and OA is 80 and 20%, respectively), which is HII throughout, with a unit cell parameter of approximately 60 Å.31 However, by increasing the content of lipid 1 (up to 5%), a slight decrease of the lattice parameter was observed. The symmetry of all investigated LMPs (LCPs and HII phases) is stable and does not change after 24 h in excess of water at pH 7.4. Increasing the content of lipid 1 above 5% (w/w) in the formulations resulted in inhomogeneous LMPs, which was visible by inspection and was determined independently by SAXS. We assume that the conformational flexibility of the terminal azobenzene moieties of lipid 1 can perturb the ordered bilayer structures of the MO scaffold and that this effect is dependent upon the relative amount of lipid 1. Thus, at levels above 5% (w/w), the system is disordered to an extent that it is unable to form ordered aggregates in water. We therefore carried out all release experiments with a maximal amount of lipid 1 embedded in the LMPs, which is 5% (w/w). Release Experiments. Experiments with MG in LCPs composed of MO/1/PBS = 59:1:40 (%, w/w) demonstrate a fast release of the hydrophilic dye in the absence of electrostatic interactions between the lipid head groups and the dye embedded in the aqueous channels, with 45% of the dye released within 8 h. These results are in perfect agreement with the control of release via host−guest electrostatic interactions in cubic phases reported recently.7,34 Upon the addition of the anionic lipid OA at levels of 1 and 5% (w/w) into the LCPs at pH 7.4, the negatively charged carboxylate headgroup binds the dye more efficiently than the neutral glycerol headgroup of MO (Figure 2). Increasing the amount of OA from 1 to 5% does not alter the release profile, because already at a level of 1%, the binder (OA) is in large excess with respect to the positively charged dye (nOA/nMG = 364:1). On the basis of these results, formulations containing 1% OA were employed in subsequent light-triggered release experiments. Photochemical triggering of drug release represents a powerful alternative to conventional methods, provided that the medium is transparent. Photoinduced isomerization of lipid 1 was characterized spectroscopically in acetonitrile, before and after exposure to UV and visible light for 15 min. Before irradiation, the trans form of lipid 1 exhibits a maximum absorption band at around 330 nm. This absorbance peak decreased following UV irradiation because of trans−cis isomerization. Concomitantly, a weak absorption band at ca. 440 nm, which is based on the n−π* transition of the cis isomer,35 confirmed the trans−cis isomerization. The degree of isomerization from trans to cis for lipid 1 was 70% (see Figure S1 of the Supporting Information and eq 1). Following UV irradiation, the sample was irradiated with visible light for 15 min and the spectrum was recorded. The original spectrum is not completely recovered, as evidenced by the maximum absorption band at ca. 330 nm, indicating an incomplete

Table 1. Samples, Phase Identity, and Crystallographic Unit Cell Parameters Observed for Mixed LCPs sample MO/1/PBS, 59:1:40 (%, w/w), empty MO/1/PBS, 59:1:40 (%, w/w), MG cargo MO/1/OA/PBS, 58:1:1:40 (%, w/w), empty MO/1/OA/PBS, 58:1:1:40 (%, w/w), MG cargo MO/1/OA/PBS, 54:1:5:40 (%, w/w), empty MO/1/OA/PBS, 54:1:5:40 (%, w/w), MG cargo

phase identity

unit cell (Å)

Pn3m Pn3m Pn3m Pn3m

98.7 98.4 95.5 95.6

Pn3m Pn3m

94.5 94.7

Table 2. Samples, Phase Identity, and Crystallographic Unit Cell Parameters Observed for Mixed LMPs phase identity

unit cell (Å)

55.3:0.7:14:30 (%, w/w),

HII

59.7

55.3:0.7:14:30 (%, w/w), MG

HII

60.0

52.5:3.5:14:30 (%, w/w),

HII

60.0

52.5:3.5:14:30 (%, w/w), MG

HII

59.8

51:5:14:30 (%, w/w), empty 51:5:14:30 (%, w/w), MG

HII HII

54.2 54.8

sample MO/1/OA/PBS, empty MO/1/OA/PBS, cargo MO/1/OA/PBS, empty MO/1/OA/PBS, cargo MO/1/OA/PBS, MO/1/OA/PBS, cargo

Figure 2. Percentages of MG release as a function of the square root of the time from the aqueous compartments of the following LCPs into the overlay: MO/1/PBS = 59:1:40 (black squares), MO/1/OA/PBS = 58:1:1:40 (red circles), and MO/1/OA/PBS = 54:1:5:40 (blue triangles). Mean ± standard deviation (SD) (n = 3).

istic of the long-range positional order are detected. SAXS experiments were carried out on either empty mesophases or on the formulations that contain dyes (MG, 0.1 mM). Additionally, OA was embedded at 1 and 5% (w/w) in the LMPs to introduce a negative charge into the bilayer, which can potentially bind a positively charged dye.34 Table 1 summarizes the SAXS results. In all investigated samples, functionalization of the mesophase by the addition of the synthetic guest lipid and the positively charged dye (MG) at the levels used did not affect the phase identity and unit cell size of the MO/H2O system, which was Pn3m throughout, with a unit cell parameter of approximately 100 Å.1 These results are in good agreement with our previously published work.7 6983

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Figure 3. Percentages of MG release as a function of time from the aqueous compartments of the following LCPs into the overlay: MO/1/OA/PBS = 58:1:1:40 in the dark (diamonds) and following sequential exposure to UV and visible light marked with blue and red arrows, respectively (triangles), for 15 min: (a) UV illumination after 2, 4, and 6 h and (b) UV illumination immediately after LCP preparation and after 4 h. Mean ± SD (n = 3). The insets show the ratio between the diffusion coefficient after irradiation (DUV) and the diffusion coefficient in the dark (D0) plotted versus the square root of the time, up to 3 h.

Figure 4. Percentages of MG release as a function of time from the aqueous compartments of the following mesophases into the overlay: (a) MO/1/ OA/PBS = 55.3:0.7:14:30 (%, w/w) (HII; circles) and MO/1/OA/PBS = 58:1:1:40 (%, w/w) (Pn3m LCP; squares) in the dark and (b) MO/1/ OA/PBS = 55.3:0.7:14:30 (%, w/w) in the dark (HII; circles) and after sequential exposure to UV (blue arrows) and visible light (red arrows) for 15 min (HII; triangles). Mean ± SD (n = 3). The inset shows the ratio between the diffusion coefficient after irradiation (DUV) and the diffusion coefficient in the dark (D0) plotted versus the square root of the time, up to 4 h.

Table 3. Samples, Phase Identity, Crystallographic Unit Cell Parameters, Lipid Chain Length (LLip), and Radius (r) of the Water Channel Observed for Mixed LMPs sample MO/1/OA/PBS = 51:5:14:30 (%, w/w) (before UV) MO/1/OA/PBS = 51:5:14:30 (%, w/w) (after UV)

phase identity

unit cell (Å) Llip (Å)

r (Å)

HII

54.78

12.06

15.33

HII

54.82

12.07

15.34

(≅75%) isomerization under alternating UV and visible light irradiation. Lipid 1 was incorporated into MO-based LCPs [MO/1/OA/PBS = 58:1:1:40 (%, w/w)], and release profiles from the LCPs under various conditions were measured (Figure 3). Following 2 h in the dark, lipid 1-doped LCP was exposed to UV light for 15 min (marked with a blue arrow in Figure 3a). The trans-to-cis isomerization of the azobenzene moiety is accompanied by release of MG. As described, the isomerization is reversible; subsequent exposure to visible light

Figure 5. Percentages of MG release as a function of the square root of the time from the aqueous compartments of the following HII phases into the overlay: MO/1/OA/PBS with 0.7, 3.5 and 5% of 1 (white triangles, black triangles, and black circles, respectively) after sequential exposure to UV (blue arrows) and visible light (red arrows) for 15 min. Mean ± SD (n = 3).

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Figure 6. (a) Schematic structural changes of the azobenzene moiety upon UV irradiation at the molecular level. (b) SAXS spectra before and after UV irradiation.

for 15 min after 3 h (marked with a red arrow) reverts the trans configuration of the azobenzene lipids, resulting in abortion of the release of dye into the overlay. Significantly, this effect can be repeated, and further exposure to UV radiation for 15 min after 4 and 6 h results in an additional release of MG, whereas the release is stopped following irradiation with visible light. In a similar experiment, shown in Figure 3b, immediate exposure of the lipid 1-doped LCP to UV light for 15 min after overlaying the LCP with 1 mL of PBS at pH 7.4 initiates a trans-to-cis isomerization of the azobenzene group, which is accompanied by release of MG. As expected, the isomerization is reversible, so that subsequent exposure after 2 h to visible light for 15 min reverts the configuration of azobenzene to trans, resulting in a decrease of the dye released into the overlay. These processes can be performed sequentially, thereby achieving both temporal and dosage control. To decrease the amount of dye released from mesophases without irradiation (up to 2 h), hexagonal phases (HII) composed of MO/1/OA/PBS = 55.3:0.7:14:30 (%, w/w) were employed. As expected, without irradiation, release from the HII phase is slower that from the cubic Pn3m phase (Figure 4a).4,24 In a parallel experiment, lipid 1-doped mesophases were kept for 2 h in the dark, followed by exposure to UV light for 15 min (marked with a blue arrow in Figure 4b). The trans-to-cis isomerization of the azobenzene moiety is accompanied by release of MG. Here, again, the isomerization is reversible; subsequent exposure to visible light for 15 min after 4 h (marked with a red arrow) reverts the azobenzene lipids to the trans configuration, resulting in abortion of the release into the overlay. This effect can be repeated, and further exposure to UV radiation for 15 min after 6 h results in additional release of MG. Further experiments were carried out to investigate a possible correlation between the percentage of lipid 1 embedded in the LMPs and the degree of dye release from the mesophases following UV irradiation. The concentration of lipid 1 was varied between 0.7 and 5%, and in all cases, the trans-to-cis isomerization of the azobenzene moiety is accompanied by release of MG, as shown in Figure 5. However, the release profile for the MO/1/OA/PBS is independent of the amount of lipid 1 present in the membrane, in both the dark and following light exposure. Structural Changes in the LMPs Following UV Irradiation. To evaluate the effect of UV irradiation of lipid 1 on the phase identity and structural parameters of the host− guest LMP system, mesophases were prepared and analyzed

with SAXS. SAXS experiments were performed on the formulation doped with guest lipids immediately after preparation and after 15 min of UV exposition. As shown in Table 3, the trans-to-cis isomerization of lipid 1 at 5% (w/w) content does not affect the phase identity of the LMPs. Thus, the significant conformational change of the terminal region of lipid 1 does not induce a change of either the lattice parameter or the length of the lipid bilayer and the radius of the aqueous channel (Table 3). One possible explanation is that UVinduced changes in the azobenzene conformation are partially dissipated by the flexibility of the chain,35,36 because the azobenzene group of 1 is attached to the end of a flexible unsaturated hydrocarbon chain. An alternative explanation would be that the structural changes in the azobenzene moiety at the molecular level are local and do not affect the overall packing arrangement and subsequent crystallographic parameters of the mesophase, as depicted in Figure 6. Notwithstanding, lipid 1 was shown to be activated by UV, thereby undergoing isomerization with a concomitant local change in the packing and organization of the hydrophobic region of the lipid bilayer and resulting triggered release (see Figure 5). Because the cis form is more hydrophilic and presents a different length of the hydrophobic part compared to the trans form,37 these differences would be sufficient to change the nature of the hydrophobic layer, thereby affecting the lipid− water partition coefficient of the drug, control the permeability of the membrane, which is in line with recent findings,23 and induce controlled release of the dye after UV irradiation. These findings are in stark contrast to the photochemical response of mesophases composed of alkylated spiropyran molecules, which undergo reversible cubic to reversed hexagonal phase transitions.6 Finally, another regime is obtained with mesophase systems that contain o-nitrobenzyl-derivatized lipids.7 These undergo irreversible photochemical cleavage reactions that can switch the charge of their headgroups, thereby affecting binding and release of the drug molecules.

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CONCLUSION

A novel light-responsive functional lyotropic liquid crystal system using host−guest LMPs was designed, synthesized, and characterized. These biomaterials consist of the host lipids MO and OA and a small amount of a judiciously synthesized azobenzene-derivatized lipid as the photoactive guest unit. The phase identity and unit cell parameters of the materials were established by SAXS. Light as an external stimulus has many advantages in comparison to other stimuli; it is milder than 6985

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(10) Brancaleon, L.; Moseley, H. Laser and non-laser light sources for photodynamic therapy. Lasers Med. Sci. 2002, 17 (3), 173−186. (11) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013, 12 (11), 991−1003. (12) Jiang, J.; Tong, X.; Morris, D.; Zhao, Y. Toward photocontrolled release using light-dissociable block copolymer. Macromolecules 2006, 39 (13), 4633−4640. (13) Lee, H. M.; Larson, D. R.; Lawrence, D. S. Illuminating the chemistry of life: Design, synthesis, and applications of “caged” and related photoresponsive compounds. ACS Chem. Biol. 2009, 4 (6), 409−427. (14) Hartley, G. S. The cis-form of azobenzene. Nature 1937, 140, 281. (15) Bradley, M.; Vincent, B.; Warren, N.; Eastoe, J.; Vesperinas, A. Photoresponsive surfactants in microgel dispersions. Langmuir 2006, 22 (1), 101−105. (16) Eastoe, J.; Dominguez, M. S.; Cumber, H.; Wyatt, P.; Heenan, R. K. Light-sensitive microemulsions. Langmuir 2004, 20 (4), 1120− 1125. (17) Eastoe, J.; Sanchez-Dominguez, M.; Wyatt, P.; Heenan, R. K. A photo-responsive organogel. Chem. Commun. 2004, 22, 2608−2609. (18) Klohs, J.; Wunder, A.; Licha, K. Near-infrared fluorescent probes for imaging vascular pathophysiology. Basic Res. Cardiol. 2008, 103 (2), 144−151. (19) Brambilla, D.; Luciani, P.; Leroux, J. C. Breakthrough discoveries in drug delivery technologies: The next 30 years. J. Controlled Release 2014, 190, 9−14. (20) Guo, C.; Wang, J.; Cao, F.; Lee, R. J.; Zhai, G. Lyotropic liquid crystal systems in drug delivery. Drug Discovery Today 2010, 15 (23− 24), 1032−1040. (21) Luzzati, V.; Husson, F. Structure of liquid-crystalline phases of lipid-water systems. J. Cell Biol. 1962, 12 (2), 207−219. (22) Kulkarni, C. V.; Wachter, W.; Iglesias-Salto, G.; Engelskirchen, S.; Ahualli, S. Monoolein: A magic lipid? Phys. Chem. Chem. Phys. 2011, 13 (8), 3004−3021. (23) Martiel, I.; Baumann, N.; Vallooran, J. J.; Bergfreund, J.; Sagalowicz, L.; Mezzenga, R. Oil and drug control the release rate from lyotropic liquid crystals. J. Controlled Release 2015, 204, 78−84. (24) Phan, S.; Fong, W.-K.; Kirby, N.; Hanley, T.; Boyd, B. J. Evaluating the link between self-assembled mesophase structure and drug release. Int. J. Pharm. 2011, 421 (1), 176−182. (25) Chen, Y.; Ma, P.; Gui, S. Cubic and hexagonal liquid crystals as drug delivery systems. BioMed Res. Int. 2014, 2014, 815981. (26) Briggs, J.; Chung, H.; Caffrey, M. The temperature-composition phase diagram and mesophase structure characterization of the monoolein/water system. J. Phys. II 1996, 6 (5), 723−751. (27) Milak, S.; Zimmer, A. Glycerol monooleate liquid crystalline phases used in drug delivery systems. Int. J. Pharm. 2015, 478 (2), 569−587. (28) Landau, E. M.; Luisi, P. L. Lipidic cubic phases as transparent, rigid matrices for the direct spectroscopic study of immobilized membrane proteins. J. Am. Chem. Soc. 1993, 115 (6), 2102−2106. (29) Yaghmur, A.; Rappolt, M. Structural characterization of lipidic systems under nonequilibrium conditions. Eur. Biophys J. 2012, 41 (10), 831−840. (30) Osornio, Y. M.; Uebelhart, P.; Bosshard, S.; Konrad, F.; Siegel, J. S.; Landau, E. M. Design and synthesis of lipids for the fabrication of functional lipidic cubic-phase biomaterials. J. Org. Chem. 2012, 77 (23), 10583−10595. (31) Lopes, L. B.; Ferreira, D. A.; de Paula, D.; Garcia, M. T.; Thomazini, J. A.; Fantini, M. C.; Bentley, M. V. Reverse hexagonal phase nanodispersion of monoolein and oleic acid for topical delivery of peptides: In vitro and in vivo skin penetration of cyclosporin A. Pharm. Res. 2006, 23 (6), 1332−1342. (32) Mezzenga, R.; Meyer, C.; Servais, C.; Romoscanu, A. I.; Sagalowicz, L.; Hayward, R. C. Shear rheology of lyotropic liquid crystals: A case study. Langmuir 2005, 21 (8), 3322−3333.

acids or bases, and variation of intensity and duration can provide a high level of pharmacological control. The effectiveness of the investigated materials in release and retention of embedded dye molecules in single-step and sequential light triggering was demonstrated, thereby achieving exquisite temporal, spatial, and dosage control of the release. This opens up the possibility of using such lipidic biomaterials as effective matrices in therapy, when a continuous release of active drugs might be toxic. Moreover, because of the thermodynamic stability of fully hydrated mesophases with any amount of excess water and their soft gel consistency, we envisage the possibility of applying such nanostructured biomaterials to specific locations in vivo. Finally, because of the ability of LMPs to incorporate molecules of any polarity or charge, the strategy presented here is general, i.e. moleculeindependent, and shows great promise for various biomedical applications.

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ASSOCIATED CONTENT

S Supporting Information *

Spectra before and after UV and visible irradiation of lipid 1 (in CHCl3 solution) and SAXS spectra of mesophases. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.5b01945.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by the Polish−Swiss Joint Research Programme Grant PSPB-079/2010 to Ehud M. Landau.

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REFERENCES

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DOI: 10.1021/acs.langmuir.5b01945 Langmuir 2015, 31, 6981−6987

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DOI: 10.1021/acs.langmuir.5b01945 Langmuir 2015, 31, 6981−6987