Monodisperse Nonionic Isoprenoid-Type Hexahydrofarnesyl Ethylene

Feb 4, 2011 - Xavier Mulet , Charlotte E. Conn , Celesta Fong , Danielle F. ... Nigel Kirby , David K. Wright , Hong X. Wang , Gary F. Egan , Bradford...
0 downloads 0 Views 1MB Size
Download PDF
ARTICLE pubs.acs.org/Langmuir

Monodisperse Nonionic Isoprenoid-Type Hexahydrofarnesyl Ethylene Oxide Surfactants: High Throughput Lyotropic Liquid Crystalline Phase Determination Celesta Fong,*,† Asoka Weerawardena,† Sharon M. Sagnella,‡ Xavier Mulet,†,§ Irena Krodkiewska,† Josephine Chong,†,§ and Calum J. Drummond† †

CSIRO Materials Science & Engineering (CMSE), Bag 10, Clayton South, VIC 3169, Australia CMSE, PO Box 184, North Ryde, NSW 1670, Australia § Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia ‡

bS Supporting Information ABSTRACT: The neat and lyotropic phase behavior of eight new ethylene oxide amphiphiles (EO = 1-8) with a hexahydrofarnesyl chain (3,7,11trimethyldodecyl) and narrow polydispersity (>98.5% purity) is reported. Below five EO units the behavior of the neat surfactants show only a glass transition, Tg ∼ -90 °C. Above four EO units, crystallization (Tcrys) and crystal-isotropic liquid (Tm) transitions are also observed that increase with degree of ethoxylation of the surfactant headgroup. The lyotropic liquid crystalline phase behavior spans a complex spectrum of surfactant-water interfacial curvatures. Specifically, inverse phases are present below ambient temperatures for EO < 4, with HFarn(EO)2 exhibiting an inverse hexagonal (HII) phase stable to dilution. The phase diagram of HFarn(EO)3 displays both the gyroid (Ia3d) and double diamond (Pn3m) inverse bicontinuous cubic phases, with the latter being thermodynamically stable in excess water within the physiological regime. There is a strong preference for planar bilayer structures at intermediate headgroup ethoxylation, with the crossover to normal phases occurring at HFarn(EO)7-8 which exhibits normal hexagonal (HI) and cubic (QI) phases at ambient temperatures. The toxicity of colloidal dispersions of these EO amphiphiles was assayed against normal breast epithelial (HMEpiC) and breast cancer (MCF7) cell lines. The IC50 of the EO amphiphiles was similar in both cell lines with moderate toxicity ranging from ca. 98%.25 Thermal Analysis. DSC measurements were performed on a Mettler DSC30 system. Neat samples weighing 5-15 mg were sealed in aluminum pans (25 μL) with pierced lids and heated or cooled at a scan rate between 2.5 and 15 °C min-1. Thermograms were recorded in a nitrogen atmosphere, using empty aluminum pans as the reference. The calibration of temperature and enthalpy scales was achieved using octane and indium standards. Cloud Point Determination. A 1% w/w aqueous solution of each surfactant was prepared and equilibrated at 5 °C prior to heating or cooling at 0.5 °C/min. The solution was monitored visually for haziness and the cloud point assigned based upon the first appearance or disappearance of turbidity. The cited cloud points are an average of a minimum of three readings.

Water Penetration into HFarnesyl Ethylene Oxide Amphiphiles. Optical textures were observed with an Olympus IMT-2 crosspolarized optical microscope equipped with a Mettler FP82HT hot stage and a FP90 programmable temperature controller. Samples were cooled below ambient temperature by flowing air cooled over liquid nitrogen through the hot stage. Images were captured with an Olympus c-5060 digital camera (Olympus Australia Pty. Ltd., Melbourne, Australia). Samples were typically heated at a scan rate of 2-5 °C/min from 1 to 85 °C unless otherwise stated.

DIT-NIR Microspectroscopy for High Throughput Phase Mapping. This method has been described in detail by Laughlin et al.26,27 as well as in a companion paper to the current work.25 Nearinfrared spectra were collected using a Perkin-Elmer Spectrum 2000 (Beaconsfield, UK) spectrometer fitted with AutoImage microscope and SPECTRUM software v5.00. Sample temperature was controlled with a Linkam hot stage and controller (LTS 120 with PE94 controller, Linkam UK) fitted with manual micrometers for adjustment of sample position. The spectrometer was modified for use in the near-infrared by the use of a quartz beam splitter and liquid nitrogen cooled In/Sb detector. Apertures of 50  50 μm or 100  100 μm were used to define the regions of interest at the boundary of the interface between two phases as viewed through cross-polarized microscopy. Interferograms were coadded (up to 64 scans) using a scan resolution of 4 cm-1 in the frequency range 4000-6500 cm-1. The peak area of the bend-stretch combination band of water at ∼5200 cm-1 was used to determine the water composition against a calibration curve with C8PO which obeyed the Beer-Lambert law. DIT-NIR studies were conducted in quartz cells (Starna Pty Ltd.). The liquid surfactant was loaded at one end by wicking into the cell using capillary action. The cell was permitted to equilibrate for up to 12 h to allow the formation of the mesophases for identification by LPM. The approximate partial phase diagrams obtained by DIT-NIR microspectropscopy was performed in the heating direction. Preparation of Colloidosome Dispersions. Dispersions of the ethylene oxide surfactants were prepared using a miniextruder (Avanti Polar Lipids). Dispersions of F127 (0.45% w/w, from BASF Corp.) dissolved in water and surfactant (5% w/w) were passed through 400 μm polycarbonate membranes for a minimum of 20 passes. Cytotoxicity of Colloidosome Dispersions. The toxicity of the ethylene oxide nanoparticles was evaluated against two different cell types: MCF-7 (human breast cancer cell line; American Tissue Type Collection) and HMEpiC (primary human mammary epithelial cells; ScienCell). Details of cell culture have been described previously.25 For toxicity assays, cells were seeded into the wells of a 96-well plate at a density of 10 000 cells/well and maintained at 37 °C, 5% CO2 incubator (IR Sensor CO2 incubator, Sanyo, Japan) for 24 h to allow the cells to 2318

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir

ARTICLE

Table 1. Solid-State Behavior of the HFarnesyl Ethylene Oxide Amphiphiles EO

Tg(midpoint)

1

-98.9

2 3

-93.4 -90.4

4

-86.0

Tcrys(onset peak)

ΔH (J/g)

Tm(onset peak)

ΔH (J/g)

5

-79.5

-67.8, -62.6

27.0

-54.4, -45.2

-32.8

6

-79.3

-71.6, -68.6

31.2

-39.0, -32.6

-45.2

7

-80.9

-38.1, -34.4

29.5

8

-79.8

-23.1, -16.8

-73.7

-14.3, -11.4

-70.9

attach and grow to confluence. 10 μL aliquots of the nanoparticle dispersion were then added to the cells at three different concentrations (∼0.5, 0.05, and 0.005 mg/mL). The cells were again maintained at 37 °C, 5% CO2 for an additional 48 h. After 48 h, the cells were rinsed, and the number of cells was determined by measuring the conversion of a tetrazolium compound into a formazan product by the mitochondria of living cells (CellTiter 96 AQueous One Solution Cell Proliferation Assay, Promage, Australia). After ∼3 h incubation with the reagent, the absorbance was read at λ = 490 nm using a Wallac Victor 1420 multilabel counter (Perkin-Elmer Life Science). Small-Angle X-ray Scattering (SAXS). Small-angle X-ray scattering was performed to obtain verification of phase assignments from LPM and to obtain lattice parameters. Samples with discrete composition were prepared by adding a known volume of Milli-Q water to the preweighed neat surfactant. The samples were centrifuged, vortexed, and equilibrated at room temperature for a minimum of 3 days to ensure homogeneity. Dispersions were prepared as stated above, and all samples were contained in 1.5 mm glass capillaries for SAXS. A silver behenate standard was used to calibrate the reciprocal space vector. SAXS was performed in the heating direction as for DIT-NIR. Where required, samples were kept in the fridge for equilibration prior to SAXS. Data were collected using the SAXS/WAXS beamline at the Australian Synchrotron using a beam of wavelength λ = 0.80 Å (15.0 keV) with dimensions 700 μm  500 μm and a typical flux of 1.2  1013 photons/s. Sample temperature was controlled using a recirculating bath (Julabo, Gemany) with the range of accessible temperatures ∼5 to 65 °C. 2-D diffraction images were recorded on a Mar CX165 detector with analysis in the q-range 0.017-0.645 Å-1. Data reduction (calibration and integration) was performed using AXcess, a custom-written SAXS analysis program written by Dr. Andrew Heron from Imperial College, London.28 Lamellar phases give rise to diffraction peaks in the ratio (100), (200), (300), (400), ...n (n00). The two bicontinuous cubic phases observed in this the double √ study √ √are √ √ √diamond cubic (Pn3m) with peaks in the ratio 2, √3, √4, √6, 8,√ 9 and √ the√gyroid cubic (Ia3d) with peaks in the ratio 6, 8, 14, 16, 20, 22. The hexagonal phase comprises √ √ hexagonally close packed cylinders with diffraction peaks at 1, 3, 4.

’ RESULTS AND DISCUSSION Phase Behavior of the Neat HFarnesyl Ethylene Oxide Amphiphiles. The thermal transitions for the neat HFarnesyl

ethylene oxide amphiphiles are summarized in Table 1. All of these surfactants are colorless, low-viscosity liquids at room temperature. The thermally induced phase transitions are dependent upon the number of ethylene oxide units within the headgroup; specifically, these may comprise a glass transition (Tg), crystallization transition (Tcrys), and a crystal-to-isotropic liquid or melting transition (Tm) (Figure 2). All members of the

Figure 2. Representative DSC trace of HFarn(EO)7 showing characteristic thermal transitions. These comprise a glass transition (Tg midpoint -80.9 °C), crystallization (Tc peak -34.4 °C), and melting (Tm peak -16.8 °C) transitions.

Figure 3. Variation of the glass transition (9, Tg) and melting point (b, Tm) with the number of EO units in the headgroup.

series have a glass transition, and these increase more or less monotonically with the hydrophilicity of the headgroup up to five EO units, with the more hydrophilic amphiphiles (EO g 5) possessing similar values for Tg of ca. -80 °C. HFarnesyl derivatives with EO g 5 units also exhibit crystallization and crystal-to-isotropic liquid or melting transitions. These increase with the number of EO units in the headgroup. Figure 3 illustrates the variation of the Tg and Tm as a function of the number of ethylene oxide units in the headgroup. The thermal behavior of the neat ethylene oxide amphiphile is qualitatively similar for both HFarnesyl and phytanyl25 hydrophobes, although for the equivalent headgroup length, the latter demonstrates a slightly higher Tg. At the glass transition temperature the inter/intramolecular interactions of the molecule are “frozen” to form a “glassy crystal” with the same structure as the liquid crystal. This phenomenon, while more widely reported in polymers, is increasingly reported for amphiphiles.29-32 The higher Tg associated with the phytanyl analogues suggests a higher cohesive energy arising from enhanced van der Waals 2319

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir interactions within the slightly longer phytanyl chain (C16 vs C12 backbone). For EO e 5, Tg increases with the degree of ethoxylation, suggesting that the bulkier head groups interact more strongly with each other to form a “glassy crystal” more easily. However, the value of Tg is relatively unaffected by additional ethoxylation. For EO g 5 the appearance of Tcrys and Tm indicate increased ordering and crystallinity of the molecules, most likely via van der Waals interactions of the EO headgroup. This increases with each additional EO unit, although the effect of the exaggerated footprint and splay of the isoprenoidtype chain remains effective in maintaining the liquid state of these amphiphiles. A similar effect has been observed by these authors for other families of amphiphiles with the isoprenoidtype hydrophobe for head groups as diverse as glycerate, urea, and monoethanolamides.29,30,33-35 There is a nonmonotonic increase of Tcrys with increasing ethylene oxide group. This trend may reflect a change in ordering due to decreased hydrogen bonding or van der Waals interaction in the HFarn(EO)6 surfactant compared to that of the HFarn(EO)5 derivative. Lyotropic Phase Behavior of the HFarnesyl Ethylene Oxide Amphiphiles. Water penetration scans and light polarizing microscopy were used to identify the mesophases formed as a function of temperature. Optical textures of surfactant lyotropic phases have been described in detail in the literature.36 A penetration scan generates a concentration gradient spanning pure water to neat surfactant with all possible phases for the surfactant formed. Anisotropic liquid crystalline phases such as birefringent hexagonal and lamellar phases can be distinguished from isotropic phases such as cubic or micellar phases, which appear transparent under crossed polarizers. Here the assignment of normal (type 1) and inverse (type 2) phase behavior refers to the surfactant interfacial curvature either toward oil or water.37 The assignment of “inverse” phase behavior is based upon the relatively poor solubility of the surfactants and the occurrence of the hexagonal or cubic phases against the water interface which suggests their stability against dilution. Normal phases occur at low amphiphile concentration. In accordance with the usual definitions used in the literature, the assignment of these has been denoted as subscripts in the text, where QII indicates an inverse bicontinuous cubic structure and Q1 refers to the “normal” bicontinuous cubic phase. While the identification of textures is not unequivocal by this method particularly for inverse phases, the progression of phases from the interface, apparent viscosity, swelling behavior, and texture provides strong support for their correct assignment. The method therefore provides a rapid, qualitative assessment of the lyotropic phase behavior of a novel surfactant system. Table S1 summarizes the lyotropic phase behavior for the HFarnesyl ethylene oxide surfactants from LPM. Liquid crystalline phases of the EO e 2 amphiphiles were not easily observed as these had converted to mobile isotropic liquids at low temperature (T e 8 °C). Approximate partial phase diagrams of HFarn(EO)3-8 were constructed using DIT-NIR microspectroscopy (Figure 4). The DIT-NIR method is an isothermal method based on the in situ quantification of the bend-stretch combination band of water at ∼5200 cm-1 at the phase boundaries. This was achieved by calibration against a standard (e.g., octyldimethylphosphine oxide).25-27 The method is essentially a penetration scan, and as such two phase regions are not distinguishable. DIT-NIR is most effective for systems with well-defined phase boundaries. This is often not the case in these systems, particularly at the water-rich interface where anomalous swelling may occur, to

ARTICLE

result in highly mobile myelin fibrils (Figure 5d). Hence, only the approximate, partial phase diagrams are presented for HFarn(EO)3-8. DIT-NIR was not performed for HFarn(EO)1-2 as liquid crystalline phases had melted by ca. 8 °C. SAXS was performed to further verify these phases and obtain structural information. Table S2 lists the SAXS parameters of each of these systems performed at discrete compositions and temperatures. HFarn(EO)2. Flooding experiments show an anisotropic phase with fanlike texture which is attributed to an inverse hexagonal (HII) phase (Figure 5a) that melted to a mobile isotropic liquid by ca. 7.5 °C (TL2). The partial phase diagram and SAXS characterization of HFarn(EO)2 was not performed due to the low TL2 of this surfactant. HFarn(EO)3. At low temperatures (T < 2 °C) the phase behavior of HFarn(EO)3 exhibits three distinct isotropic regions in the water-rich regime. These are clearly visible from the penetration scan and are differentiated by refractive index discontinuities indicated by arrows in Figure 5b. These bands are very narrow in composition and temperature, with the two less hydrated bands merging with the outermost phase by ∼8 °C. These phases are mobile on shearing though re-form welldefined interfaces, and shear birefringence was not observed. The lamellar (LR) and isotropic phases convert to a viscous isotropic phase that is identified by “gelling” of the interface ca. 8 °C (Figure 5c). The viscous phase melts to a mobile isotropic liquid by 35-40 °C (L2). The approximate partial phase diagram of HFarn(EO)3 is presented in Figure 4a from 5 to 40 °C with SAXS used to provide assignments and structural parameters for discrete compositions and temperatures (Table S2). Two inverse bicontinuous cubic phases are present in the phase diagram of this amphiphile. These are the double diamond cubic phase (Pn3m) which is thermodynamically stable in excess water for a broad temperature window from below ambient to the physiological regime (a = 78.4 Å at 25 °C) and the gyroid cubic phase (Ia3d) which is present from ca. 22-80% w/w H2O. Interconversion between these two may occur as a function of either composition or temperature. It is anticipated that there is an Ia3d þ H2O f Pn3m þ H2O transition in the excess water regime; however, this exists below the measurement of the SAXS experiment (5 °C). A lamellar phase is also present at low to intermediate water compositions at T < 8 °C. It is anticipated that a neat Pn3m phase exists at high water content, though this was not identified. Its putative existence is included in Figure 4a for correctness. For a sample with 65% w/w H2O, SAXS confirms the progression of phases from lamellar (LR) f cubic (Ia3d) f cubic (Pn3m) f surfactant-rich liquid (L2) with increasing temperature. Figure S2a,b illustrates the 1D SAXS traces obtained from each of the bicontinuous cubic phases at 35% w/w H2O. These cubic phases give rise to “spotty” diffraction patterns, suggesting large, aligned domains within the sample. These domains give rise to inhomogeneous diffraction patterns as observed in Figure S2a. The LR phase which is clearly observed by LPM (Figure 5b,c) and defined as existing over a large composition range at low temperature (DIT-NIR) was not verified, as the lowest accessible temperature of the SAXS experiment was close to the LR f Ia3d transition. Supercooling of cubic phases is also well-known particularly in glyceryl monooleate (GMO)-water systems where the QII to Lc transition can occur 17 °C below that observed on the heating cycle.38,39 More recently, Dong et al.40 have observed nonequilibrium effects in cubosomes and hexosomes for the QII f HII transition of both GMO and phytantriol. 2320

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir

ARTICLE

Figure 4. Approximate partial phase diagrams determined from DIT-NIR microspectroscopy for (a) HFarn(EO)3, (b) HFarn(EO)4, (c) HFarn(EO)5, (d) HFarn(EO)6, (e) HFarn(EO)7, and (f) HFarn(EO)8. X marks the corresponding small-angle scattering data points acquired (see Table S2 for complete information).

Similarly, the three isotropic phases observed by LPM exist over a narrow temperature (15 wt % H2O. The stability of the lamellar phase increases with the hydrophilicity of the headgroup, with melting points of ca. 55, 57, and 70 °C observed for each of the EO = 4, 5, and 6 derivatives (from LPM)

and falls within a similar temperature range as other single- and double-chained EO surfactant systems.6 The approximate partial phase diagrams of these amphiphiles constructed from ambient temperature (20 °C) are illustrated in Figure 4b-d. Lamellar and myelinic textures are present for a broad temperature and composition window from ca. 15 wt % H2O. For a sample at 35 wt % hydration SAXS provides lattice parameters a = 42.6, 45.3, and 48.1 Å at 25 °C for EO = 4, 5, and 6, respectively. A surfactant-rich liquid (L2) is present for water compositions below 15 wt % H2O. HFarnl(EO)7-8. Approximate partial phase diagrams for HFarn(EO)7-8 are presented in Figure 4e,f from 20 °C. The lyotropic behavior of these is similar, with the sequence of phases initially observed at 5 °C: L1/H1/Q1/LR/L2 where Q1 2321

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir

ARTICLE

Figure 5. Water penetration scans of the HFarnesyl ethylene oxide amphiphiles viewed by LPM (a) HFarn(EO)2 showing an (inverse) hexagonal phase present at the interface with water at 1 °C (100). (b) HFarn(EO)3 showing the progression of phases from the water interface at 2 °C (100): Iso1/ Iso2/Iso3/LR/L2. The arrows indicate differences in refractive indices that define the interfaces between three isotropic phases. (c) HFarn(EO)3 at 7 °C showing the narrowing of Iso2/Iso3 with increasing temperature and the formation of a viscous band at the water rich boundary. (d) HFarn(EO)4 at 5 °C (100) showing the myelin textures formed by anomalous swelling at the water interface. (e) HFarn(EO)8 showing phases present at 17 °C (100): L1/H1/Q1/LR/Q2.

is attributed to a normal bicontinuous cubic phase (Figure 5e). The anisotropic phases are weakly developed and faintly birefringent. The melting point of the H1 phase is ca. 29 and 44 °C for EO = 7 and 8, respectively, with the corresponding melting points of the LR being ca. 88 and 58 °C. SAXS provides lattice parameters of the (normal) hexagonal phase (H1) of a = 63.6 Å (60 wt % H2O at 20 °C) and a = 65.1 Å (55 wt % H2O at 25 °C), and the LR phase have lattice parameters a = 43.5 Å (20 wt % H2O at 25 °C) and a =

48.2 Å (20 wt % H2O at 25 °C) for EO = 7 and 8, respectively. The isotropic phase observed between the H1 and LR was not verified from SAXS due to the narrow composition window, although this has been assigned as a normal bicontinuous cubic phase (Q1) based upon the observed sequence of phases from LPM.37 Effect of Increasing EO Headgroup Length on Lyotropic Phase Behavior. The effect on the lyotropic phase behavior with increasing headgroup length is generally analogous to the 2322

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir phytanyl series.25 This is qualitatively rationalized in terms of the molecular geometry of the surfactants. The addition of EO units to the headgroup progressively alters the hydrophobelipophobe (HLB) balance (Figure 1, Figure S1, and Table S3). As the contribution of the headgroup relative to the isoprenoid-type chain increases, the effective geometry of the amphiphile progresses from “wedge”-shaped to cylindrical with increased ethoxylation. This manifests as a changing preference from inverse to lamellar and normal mesophases. Specifically at low ethoxylation number such as for HFarn(EO)2, the exaggerated splay of the HFarnesyl chain combined with a relatively small headgroup creates a wedge-shaped profile that favors inverse phases. HFarn(EO)2 exhibits an inverse hexagonal phase that is furthermore robust to dilution, although it is destabilized at relatively low temperatures (ca. 8 °C). The propensity of the isoprenoid-type chains to promote inverse phases and lower the temperature of phase formation has previously been demonstrated for other amphiphile classes.29,30,33-35 The addition of a single ethylene oxide unit is sufficient to subtly alter the surfactant interfacial curvature, with HFarn(EO)3 displaying two inverse bicontinuous cubic phases, namely, the gyroid phase (Ia3d) and the double diamond structure (Pn3m). At intermediate ethoxylation, more planar surfactant curvatures are favored tending toward normal type mesophases (H1 and L1) at the highest EO lengths. The ethoxylate lipids presented here display excess water points (>75 wt %) for HFarn(EO)3 which are high relative to other lipids, for example monoacylglycerols which typically have excess water points in the range 40-60 wt %. In addition, they are able to sustain inverted (type 2) phases with high lattice parameters and water contents. In particular, HFarn(EO)3 forms an Ia3d phase (65 wt % water, 15 °C) with a lattice parameter of 150 Å and a Pn3m phase (80 wt % hydration, 5 °C) with a lattice parameter of 119 Å. These values are much larger than those observed for other phytanyl chained lipids which form the Pn3m cubic phase such as phytantriol (a = 68.2 Å at 54 wt % water, 25 °C) and phytanyl ethanolamide (a = 63.5 Å, 40 wt % water, 20 °C).3,6,29 The crossover from inverse-planar-normal type lyotropic phases occurs at slightly shorter ethoxylation number, ca. EO > 3 compared to ca. EO > 4 for the phytanyl analogues,25 which possess a slightly smaller HLB than their HFarnesyl counterparts (Table S3). For the equivalent number of EO units, the phytanyl chain is better able to maintain more negative surfactant interfacial curvatures. The phytanyl chain with its increased hydrophobicity in the form of the additional -CH2CH2CH(CH3)CH3 moiety possess more steric bulk, with the elongation of the carbon backbone also contributing to the exaggerated splay of the hydrophobe footprint. These factors enable the phytanyl chain to better compensate for small adjustments in the hydrophilicity of the headgroup with increasing ethoxylation. This is amply demonstrated through comparison of the phase behavior of these two isoprenoid-type ethylene oxide amphiphiles. Specifically, the phyt(EO)2 phase diagram exhibits an inverse micellar cubic (Fd3m), while HII textures are preferred for HFarn(EO)2. QII structures are present in the HFarn(EO)3-water system, whereas the corresponding phytanyl derivative demonstrates a QII f HII transition. The inverse bicontinuous cubic structures are also accessible, albeit at elevated temperatures for the phyt(EO)5-7, and these are not observed for the analogous HFarnesyl amphiphiles. Significantly, the lamellar and inverse phases of the ethylene oxide surfactants are robust to shear, and this had been used to

ARTICLE

Table 2. Comparison of the Lyotropic Behavior of Some Ethylene Oxide-Water Amphiphiles phases (mp, °C)a

surfactant C12EO227 C12EO39 C12EO49 C12EO59 C12EO69 C12EO89 C12EO129 a

L3 (35),

Q21

cloud point (°C)

2

(37), Q2 (35), LR (22)

LR (52), L3(55) L1, H1(20), Q1 (98% purity) have been rationalized in terms of molecular geometry. In general, increasing ethoxylation provided a progression in phase behavior from negative to planar to positive surfactant bilayer curvatures that is reflected in the binary surfactantwater phase diagrams. At low ethoxylation (EO = 1-2), inverse phases are preferred while at intermediate headgroup length (EO = 4-6) lamellar phases dominate, and for EO = 7-8 normal phases are favored. The HFarnesyl chained ethylene oxide surfactants share many similarities with the n-alkyl-saturated ethylene oxide amphiphiles.8-10,13 Aqueous dispersions of self-assembled surfactants with colloidal dimensions have offered promise for the encapsulation of therapeutic ingredients for controlled/sustained release, with cubosomes from GMO (glyceryl monooleate)4,65,66 and phytantriol (3,7,11,15-tetramethylhexadecan-1,2,3-triol)59,60,67 dominating the literature in this arena. Despite the immense interest in such materials, surprisingly little consideration has been given to the systematic design and synthesis of new amphiphiles, and there are a limited number of other materials that exhibit the requisite phase behavior.29,30,33-35,52-54,68,69 In the current study we have identified rich mesomorphism for some new ethylene oxide surfactants that span a diversity of nanostructures which can form stable emulsions, cubosomes, liposomes, and micelles. Together with the potential for biocompatibility afforded by the EO headgroup, this family of amphiphiles poses interesting opportunities for drug delivery and nanomedicine and offer novel alternatives to the handful of existing amphiphiles in this arena. Further, these are likely to promote improved cell membrane penetration, resulting in enhanced efficacy of encapsulated drugs. Finally, the study presented in this article contributes to the base of knowledge required to enhance our ability to rationally use structure-property relationships to predict and develop novel surfactant systems for wide-ranging applications. ’ ASSOCIATED CONTENT

bS

Supporting Information. Tables S1-S4 and Figures S1 and S2. This material is free of charge via the Internet at http:// pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*Email: [email protected].

’ ACKNOWLEDGMENT The authors thank Mr. Darrell Wells for the synthesis of the calibrant for DIT-NIR experiments and Drs. Stephen Mudie and Nigel Kirby of the Australian Synchrotron for their assistance in the setup of the SAXS/WAXS beamline. Dr. Ken Deutscher from Huntsman is thanked for providing the polydisperse samples of HFarn(EO)n. Mr. Noel Hart and Mr. Stuart Littler are thanked for assistance with HPLC purification of these materials. C.J.D. is the recipient of an Australian Research Council Federation Fellowship. S.M.S. and X.M. are recipients of CSIRO postdoctoral fellowships and J.C. is a recipient of a CSIRO Ph.D. studentship.

ARTICLE

’ REFERENCES (1) Malmsten, M. Soft Matter 2006, 2, 760–769. (2) Drummond, C. J.; Fong, C. Curr. Opin. Colloid Interface Sci. 2000, 4, 449–456. (3) Mulet, X.; Kennedy, D. F.; Conn, C. E.; Hawley, A.; Drummond, C. J. Int. J. Pharm. 2010, 395, 290–297. (4) Sagalowicz, L.; Leser, M. E.; Watzke, H. J.; Michel, M. Trends Food Sci. Technol. 2006, 17, 204–214. (5) Yaghmur, A.; Glatter, O. Adv. Colloid Interface Sci. 2009, 333– 342. (6) Kaasgaard, T.; Drummond, C. J. Phys. Chem. Chem. Phys. 2006, 8, 4957–4975. (7) Hyde, S.; Andersson, S.; Larsson, K.; Blum, Z.; Landh, T.; Lidin, S.; Ninham, B. W. The Language of Shape. The Role of Curvature in Condensed Matter: Physics, Chemistry and Biology; Elsevier: Amsterdam, 1997. (8) Sakya, P.; Seddon, J. M.; Templer, R. H.; Mirkin, R. J.; Tiddy, G. J. T. Langmuir 1997, 13, 3706–3714. (9) Mitchell, D. J.; Tiddy, G. J. T.; Waring, L.; Bostock, T.; McDonald, M. J. Chem. Soc., Faraday Trans. 1 1983, 79, 975–1000. (10) Funari, S. S.; Holmes, M. C.; Tiddy, G. J. T. J. Phys. Chem. 1992, 96, 11029–11038. (11) Conroy, J. P.; Hall, C.; Leng, C. A.; Rendall, K.; Tiddy, G. J. T.; Walsh, J.; Lindblom, G. Prog. Colloid Polym. Sci. 1990, 82, 253–262. (12) Thompson, L.; Walsh, J. M.; Tiddy, G. J. Colloids Surf., A 1996, 106, 223–235. (13) Walsh, J. M.; Tiddy, G. T. Langmuir 2003, 19, 5586–5594. (14) Schick, M. J. Nonionic Surfactants: Physical Chemistry; Surfactant Science Series 23; Marcel Dekker: New York, 1987. (15) Hamidid, A.; Azadi, A.; Rafiei, P. Drug Deliv. 2006, 13, 399–409. (16) Andrade, J. D.; Hlady, V. Adv. Polym. Sci. 1986, 79, 1–63. (17) Jeon, S. I.; Lee, J. H.; Andrade, J. D.; De Gennes, P. G. J. Colloid Interface Sci. 1991, 142, 149. (18) Jeon, S. I.; Lee, J. J.; Andrade, J. D.; De Gennes, P. G. J. Colloid Interface Sci. 1991, 142, 159–166. (19) Larsson, K . Proc. Int. Symp. Control Rel. Bioact. Mater. 1997, 24, 198–199. (20) Spicer, P. Chem. Eng. Res. Des. 2005, 83, 1283–1286. (21) Spicer, P. T. Curr. Opin. Colloid Interface Sci. 2005, 10, 274–279. (22) Spicer, P. T.; Hayden, K. L.; Lynch, M. L.; Ofori-Boateng, A.; Burns, J. L. Langmuir 2001, 17 (19), 5748. (23) Kang, J. S.; DeLuca, P. P.; Lee, K. C. Expert Opin. Emerging Drugs 2009, 14, 363–380. (24) Immordino, M. L.; Dosio, F.; Cattel, L. Int. J. Nanomed. 2006, 297–315. (25) Fong, C.; Weerawardena, A.; Krodkiewska, I.; Sagnella, S. M.; Waddington, L. J.; Drummond, C. J. Soft Matter 2010, 6, 4727–4741. (26) Laughlin, R. G.; Lynch, M. L.; Marcott, C.; Munyon, R. L.; Marrer, A. M.; Kochvar, K. A. J. Phys. Chem. B 2000, 104, 7354–7362. (27) Lynch, M. L.; Kochvar, K. A.; Burns, J. L.; Laughlin, R. G. Langmuir 2000, 16, 3537–3542. (28) Seddon, J. M.; Squires, A. M.; Conn, C. E.; Ces, O.; Heron, A. J.; Mulet, X.; Shearman, G. C.; Templer, R. H. Philos. Trans. R. Soc., A 2006, 364, 2635–2655. (29) Sagnella, S. M.; Conn, C. E.; Krodkiewska, I.; Drummond, C. J. Soft Matter 2009, 5, 4823–4834. (30) Fong, C.; Wells, D.; Krodkiewska, I.; Weerawardena, A.; Booth, J.; Hartley, P. G.; Drummond, C. J. J. Phys. Chem. B 2007, 111, 10713–10722. (31) Kocherbitov, V.; Soderman, O. Langmuir 2004, 20, 3056–3061. (32) Boyd, B. J.; Drummond, C. J.; Krodkiewska, I.; Grieser, F. Langmuir 2000, 16, 7359–7367. (33) Fong, C.; Krodkiewska, I.; Wells, D.; Boyd, B. B.; Booth, J.; Bhargarva, S.; McDowall, A.; Hartley, P. G. Aust. J. Chem. 2005, 58, 683– 687. (34) Fong., C.; Wells, D.; Krodkiewska, I.; Hartley, P. G.; Drummond, C. J. Chem. Mater. 2006, 18, 594–597. 2325

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326

Langmuir

ARTICLE

(35) Fong, C.; Wells, D.; Krodkiewska, I.; Booth, J.; Hartley, P. G. J. Phys. Chem. B 2007, 111, 1384–1392. (36) Rosevear, F. B. J. Am. Oil Chem. Soc. 1954, 31, 628–638. (37) Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. J. Chem. Soc., Faraday Trans. 2 1976, 72, 1525–1568. (38) Clogston, J.; Rathman, J.; Tomasko, D.; Walker, H.; Caffrey, M. Chem. Phys. Lipids 2000, 107, 191–220. (39) Qui, H.; Caffrey, M. Biomaterials 2000, 21, 223–234. (40) Dong, Y.-D.; Tilley, A. J.; Larson, I.; Lawrence, M. J.; Amenitsch, H.; Rappolt, M.; Hanley, T.; Boyd, B. J. Langmuir 201010.1021/la904803c. (41) Malmsten, M. J. Dispersion Sci. Technol. 2007, 28, 63–72. (42) Huang, S.-L. Adv. Drug Delivery Rev. 2008, 60, 1167–1176. (43) Malam, Y.; Loizidou, M.; Seifalian, A. M. Trends Pharmacol. Sci. 2009, 30, 592–599. (44) Fitzgerald, P. A. Solution Behaviour of Polyethylene Oxide Nonionic Gemini Surfactants; University of Sydney: Sydney, 2002. (45) Briggs, J.; Caffrey, M. Biophys. J. 1994, 67, 1594–1602. (46) Briggs, J.; Caffrey, M. Biophys. J. 1994, 66, 573–587. (47) Chung, H.; Caffrey, M. Biophys. J. 1995, 69, 1951–1963. (48) Qui, H.; Caffrey, M. Chem. Phys. Lipids 1999, 100, 55–79. (49) Wells, D.; Fong, C.; Drummond, C. J. J. Phys. Chem. B 2006, 110, 12660–12665. (50) Wells, D.; Fong, C.; Krodkiewska, I.; Drummond, C. J. J. Phys. Chem. B 2006, 110, 5112–5119. (51) Hato, M.; Minamikawa, H. Langmuir 1996, 12, 1658–1665. (52) Hato, M.; Minamikawa, H.; Salkar, R. A.; Matsutani, S. Langmuir 2002, 18, 3425–3429. (53) Hato, M.; Minamikawa, H.; Tamada, K.; Baba, T.; Tanabe, Y. Adv. Colloid Interface Sci. 1999, 80, 233–270. (54) Minamikawa, H.; Hato, M. Langmuir 1997, 13, 2564–2571. (55) Salkar, R. A.; Minamikawa, H.; Hato, M. Chem. Phys. Lipids 2004, 127, 65–75. (56) Sagnella, S. M.; Conn, C. E.; Krodkiewska, I.; Moghadam, M.; Drummond, C. J. J. Phys. Chem. B 2010, 114, 1729. (57) Sagnella, S. M.; Conn, C. E.; I. Krodkiewska, I.; Moghaddam, M.; Seddon, J. M.; Drummond, C. J. Langmuir 2010, 26, 3084–3094. (58) Compain, D. L’oreal SA, FR2899462-A1. In Cosmetic/dermatological composition useful e.g. as a skin care, make-up, solar protection or hair care product, comprises an organic lipophilic UV filter and phytantriol in the form of cubic gel particles. (59) Biatry, B. L’oreal SA; US2002048593-A1. In Cosmetic or dermatological compsns. contg. phytantriol. (60) Mclain, V. C. Int. J. Toxicol. 2007, 26, 107–114. (61) Sagnella, S. M.; Kligman, F.; Anderson, E. H.; King, J. E.; Murugesan, G.; Marchant, R. E.; Kottke-Marchant, K. Biomaterials 2004, 25, 1249–1259. (62) Sagnella, S.; Anderson, E.; Sanabria, N.; Marchant, R. E.; Kottke-marchant, K. Tissue Eng. 2005, 11, 226. (63) Martina, M. S.; Nicolas, V.; Wilhelm, C.; Meenager, C.; Barratt, G.; Lesieur, S. Biomaterials 2007, 28, 4143–4153. (64) Tang, N.; Du, G. J.; Wang, N.; Liu, C. C.; Hang, H. Y.; Liang, W. J. Natl. Cancer Inst. 2007, 99, 1004–1015. (65) Ganem-Qunitanar, A.; Quintanar-Guerrero, D.; Buri, P. Drug Dev. Ind. Pharm. 2000, 26, 809–820. (66) Boyd, B. J. Int. J. Pharm. 2003, 239–247. (67) Dong, Y. D.; Larson, I.; Hanley, T.; Boyd, B. J. Langmuir 2006, 22, 9512–9518. (68) Hato, M. Curr. Opin. Colloid Interface Sci. 2001, 6, 268–276. (69) Abraham, T.; Hato, M.; Hirai, M. Biotechnol. Prog. 2005, 21, 255–262.

2326

dx.doi.org/10.1021/la104736u |Langmuir 2011, 27, 2317–2326