Lanthanide phytanates: Liquid-crystalline phase behavior, colloidal particle dispersions, and potential as medical imaging agents

Article abstract of DOI:10.1021/la904006q

Lanthanide salts of phytanic acid, an isoprenoid-type amphiphile, have been synthesized and characterized. Elemental analysis and FTIR spectroscopy were used to confirm the formed product and showed that three phytanate anions are complexed with one lanthanide cation. The physicochemical properties of the lanthanide phytanates were investigated using DSC, XRD, SAXS, and cross-polarized optical microscopy. Several of the hydrated salts form a liquid-crystalline hexagonal columnar mesophase at room temperature, and samarium(III) phytanate forms this phase even in the absence of water. Select lanthanide phytanates were dispersed in water, and cryo-TEM images indicate that some structure has been retained in the dispersed phase. NMR relaxivity measurements were conducted on these systems. It has been shown that a particulate dispersion of gadolinium(III) phytanate displays proton relaxivity values comparable to those of a commercial contrast agent for magnetic resonance imaging and a colloidal dispersion of europium(III) phytanate exhibits the characteristics of a fluorescence imaging agent.

Full text of DOI:10.1021/la904006q

pubs.acs.org/Langmuir
©
2009 American Chemical Society
Lanthanide Phytanates: Liquid-Crystalline Phase Behavior, Colloidal
Particle Dispersions, and Potential as Medical Imaging Agents
†
†,
†
Charlotte E. Conn, Venkateswarlu Panchagnula, Asoka Weerawardena, Lynne
‡
†
,†,§
J. Waddington, Danielle F. Kennedy, and Calum J. Drummond*
†
CSIRO Molecular and Health Technologies (CMHT), Private Bag 10, Clayton South MDC, VIC 3169,
Australia, CSIRO Molecular and Health Technologies (CMHT), 343 Royal Parade, Parkville, VIC 3052,
‡
§
Australia, CSIRO Materials Science and Engineering (CMSE), Private Bag 33, Clayton South MDC,
VIC 3169, Australia. Current address: Chemical Engineering Division, National Chemical Laboratory,
Dr. Homi Bhabha Rd, Pune, India 411 008.
Received October 21, 2009. Revised Manuscript Received November 29, 2009
Lanthanide salts of phytanic acid, an isoprenoid-type amphiphile, have been synthesized and characterized.
Elemental analysis and FTIR spectroscopy were used to confirm the formed product and showed that three phytanate
anions are complexed with one lanthanide cation. The physicochemical properties of the lanthanide phytanates were
investigated using DSC, XRD, SAXS, and cross-polarized optical microscopy. Several of the hydrated salts form a
liquid-crystalline hexagonal columnar mesophase at room temperature, and samarium(III) phytanate forms this phase
even in the absence of water. Select lanthanide phytanates were dispersed in water, and cryo-TEM images indicate that
some structure has been retained in the dispersed phase. NMR relaxivity measurements were conducted on these
systems. It has been shown that a particulate dispersion of gadolinium(III) phytanate displays proton relaxivity values
comparable to those of a commercial contrast agent for magnetic resonance imaging and a colloidal dispersion of
europium(III) phytanate exhibits the characteristics of a fluorescence imaging agent.
Introduction
The self-assembly of soap molecules into liquid-crystalline
mesophases can be described in terms of the concept of the self-
assembly of amphiphiles advanced by Israelachvili et al. and is
governed by the effective shape of the molecule, which is strongly
influenced by the competing interactions of the polar headgroups
Metal-containing liquid-crystalline mesophases, or metallome-
sogens, are of interest because of their potential applications in
areas as wide-ranging as liquid-crystal displays, porous material
templating, electrochemical cells, and recently, as contrast agents
1
4
1
-6
and the alkyl chains. This can be semiquantified using the
in medical imaging. Commonly encountered metallomesogens
are metal-containing salts of long-chain fatty acids, commonly
known as “metal soaps”. Alkali and transition-metal soaps have
concept of the critical packing parameter, CPP = ν/(l a ), where
c
0
l is the effective length of an amphiphilic chain, a is the effective
c
0
7
-9
amphiphilic headgroup area, and ν is the average volume occu-
pied by the amphiphilic hydrophobic chain. Molecules with a
packing parameter of <1 will preferentially form normal phases,
and those with a packing parameter of >1 (i.e., molecules with an
effective reverse wedge shape) will preferentially form inverse
phases.
A variety of mesophases may be adopted, including a flat
bilayer or lamellar structure as well as more highly curved phases
of cubic or hexagonal symmetry. The inverse bicontinuous cubic
been widely studied.
However, similar research into the
lanthanide salts of long-chain surfactants, especially their lyotro-
pic behavior, has received far less attention, although those for
1
,10
lanthanide complexes have been covered extensively. Interest-
ingly, one of the earliest studies reporting the lyotropic behavior
of lanthanide(III) sulfates stemmed from the fact that these were
used as starting materials for the synthesis of liquid-crystalline
1
1,12
Schiff’s base complexes of lanthanides.
We note that although
lanthanidesalts of amphiphiles have been reportedpreviously, the
discovery of their mesomorphic behavior is of recent origin.
1
3
phases (Q ) consist of a single continuous bilayer draped over a
II
minimal surface of zero meancurvature that subdivides space into
two interpenetrating but not connected water networks. Three
types of inverse cubic phases have been identified in lipid
*
Corresponding author. E-mail: calum.drummond@csiro.au.
1) Binnemans, K.; Gorller-Walrand, C. Chem. Rev. 2002, 102, 2303.
2) Bottrill, M.; Nicholas, L. K.; Long, N. J. Chem. Soc. Rev. 2006, 35, 557.
3) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev. 1999,
(
(
(
15
systems. These are based on the Schwarz diamond (D) and
9
9, 2293.
(
(
primitive (P) and on the Schoen gyroid (G) minimal surfaces and
D
P
G
16
4) Raimondi, M. E.; Seddon, J. M. Liq. Cryst. 1999, 26, 305.
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Mater. Forum II 2004, 455-456, 527.
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8) Binnemans, K. Chem. Rev. 2005, 105, 4148.
are denoted as QII , QII , and QII , respectively. The main
structure observed for the lanthanide phytanates studied here is a
hexagonal columnar mesophase consisting of long cylinders of
polar headgroups with hydrocarbon chains radiating outward
and packed onto a 2D hexagonal lattice (Figure 1C). In the
presence of water, this type of structure is also known as an
(
(
(
(
75.
(
9) Giroudgodquin, A. M.; Maitlis, P. M. Angew. Chem., Int. Ed. Engl. 1991, 30,
3
3
10) Piguet, C.; Bunzli, J. C. G.; Donnio, B.; Guillon, D. Chem. Commun. 2006,
inverse hexagonal mesophase (H ). Soap molecules can also form
II
755.
(
11) Binnemans, K.; Van Deun, R.; Bruce, D. W.; Galyametdinov, Y. G. Chem.
Phys. Lett. 1999, 300, 509.
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Cryst. 2001, 28, 1877.
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729.
(14) Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. J. Chem. Soc., Faraday
Trans. 2 1976, 72, 1525.
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(16) Luzzati, V.; Tardieu, A.; Gulikkrz, T; Rivas, E.; Reisshus, F. Nature 1968,
220, 485.
(
(
1
6
240 DOI: 10.1021/la904006q
Published on Web 12/29/2009
Langmuir 2010, 26(9), 6240–6249

Conn et al.
Article
contrast agents approved for human use are extracellular
2
4
fluid (ECF) gadolinium-based agents such as Magnevist. The
paramagnetic gadolinium(III) ion significantly reduces both the
longitudinal and transverse proton relaxation times (T and T )
1
2
25
relative to that of pure water. Because the free gadolinium(III) ion
has been shown to be toxic in both in vivo and in vitro studies,
it is generally sequestered by chelation or encapsulation
2
6-29
3
30-32
in
biomedical applications. Commercial contrast agents such as
Magnevist, which is the gadolinium complex of diethylenetri-
2
4
amine pentaacetic acid, are all nonspecific and suffer from the
shortcomings of limited resolution and relatively low inherent
3
3
sensitivity. Here we have investigated the use of self-assembled
34
gadolinium(III)-containing systems as MRI contrast agents. This
potentially allows us to access desirable properties of the self-
Figure 1. (A) Structure of phytanic acid, (B) an energy-minimized
molecular model for Gd(III) phytanate (including one water of
hydration), and (C) the putative hexagonal columnar structure of
Gd(III) phytanate. (B, C) Gd is green, O is red, and C is gray. For
clarity, H atoms have been omitted.
assembled system, for example, the capacity to encapsulate drugs,
35,36
along with sustained release and targeted delivery.
In addition,
self-assembled phases of lamellar, cubic, and hexagonal symmetry
can be dispersed in water to form nanoparticles known as lipo-
somes, cubosomes, and hexosomes, respectively. The aqueous
interior of these colloidal particles allows for the movement of
water into and out of the framework, and their high surface area
can accommodate large numbers of paramagnetic ions. In addi-
tion, their specificity can be enhanced by modification with target-
ing molecules. Such systems could additionally be used as contrast
agents for optical fluorescence imaging, for example, for terbium-
inverse micelles where the hydrophilic headgroups are arranged
toward water cores with hydrophobic chains radiating outward.
1
7
These micelles can pack into ordered cubic arrays or form an
entirely disordered packing resulting in a fluid inverse micellar
phase, the L phase. Intermediate and swollen spongelike phases
2
have also been identified in non-lamellar-forming lipid systems,
although to our knowledge these have not yet been identified for
(III) and europium(III) ions, which are luminescent in aqueous
1
8,19
metal-containing liquid crystals.
solution and generally retain their luminescence when bound to
37
Among the lanthanide salts of amphiphilic carboxylates and
alkanoates, most notable is thepublished work byBinnemans and
co-workers, where the thermotropic behavior and the effects of
chain length and lanthanide ion size on the mesophases of
complex ligand systems.
In this article, we present an investigation of the thermal
and lyotropic behavior of lanthanide phytanates, along with
an investigation into the utility of nanoparticulate dispersions
of lanthanide phytanates as potential contrast agents for
magnetic resonance imaging. Both unsaturation and branching
are known to promote mesophase formation because of the
reduction in van der Waals attraction forces in the chain
2
0,21
straight-chain alkanoates were studied.
It was found that
the lanthanide dodecanoates have a lamellar bilayer structure in
the solid state and that mesophases formed only for light
lanthanide ions having larger ionic radii. It has also been found
that various hydrates of the metal soap or the anhydrous
analogues can be formed by tuning the pH of the metathesis
reaction displacing sodium in the alkanoates with the lanthanide
2
2,38-41
region,
and we have previously investigated lanthanide
3
4
oleates with unsaturated hydrocarbon chains. Here we have
extended our research to include the phytanate chain, an
isoprenoid-type hydrocarbon chain with four methyl substi-
tuents along its saturated hydrocarbon backbone. The struc-
ture of phytanic acid is shown in Figure 1A. We also attempt to
understand the influence of metal ion size and valency on the
mesophase formed.
1
and also by varying the chain length. A study by Corkery
investigating the effects of curvature on the liquid crystallinity
of midchain branched fatty acid salts of transition metals and
lanthanide salts showed that the Cu, Zn, Sr, and Ba salts formed a
liquid-crystalline hexagonal columnar mesophase at room tem-
perature. An increase in hexagonal cell size with increasing ionic
2
2
radius was observed.
(
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20) Jongen, L.; Binnemans, K.; Hinz, D.; Meyer, G. Liq. Cryst. 2001, 28, 1727.
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23) Aime, S.; Cabella, C.; Colombatto, S.; Crich, S. G.; Gianolio, E.; Maggioni,
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D.; Gries, H.; Mutzel, W.; Muetzel, W. NMR, X-ray and Ultrasonic Diagnostic
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Langmuir 2010, 26(9), 6240–6249
DOI: 10.1021/la904006q 6241

Article
Conn et al.
Experimental Section
Thermal Analysis. DSC measurements were performed on a
Mettler 3000 system. Solid samples weighing 5-10mg were sealed
in aluminum pans (25 μL) with pierced lids and heated or cooled
Materials. All reagents and precursor materials were pur-
chased from Sigma-Aldrich. Phytanol (3,7,11,15-tetramethylhex-
adecan-1-ol) was synthesized from phytol (3,7,11,15-tetramethyl-
-1
at scan rates of 2.5, 10, and 22.5 °C min . Thermograms were
recorded in a nitrogen atmosphere using empty aluminum pans as
the reference. An indium standard was used to calibrate the
DSC temperature ((0.3 °C) and enthalpy scale. TGA on a
microbalance was carried out in the temperature range of
2
described in the literature.
-hexadecen-1-ol) following reduction over Raney nickel as
4
2
Synthesis of Phytanic Acid (3,7,11,15-Tetramethylhexa-
decanoic Acid) by the Oxidation of Phytanol. The oxidation
of phytanol was carried out according to the established proto-
cols with minor modifications. Phytanol (30 g) was dissolved in
0 mL of acetic acid and 1200 mL of acetone. A solution of 24 g of
chromium trioxide dissolved in 30 mL of water was added
dropwise to the above solution placed in an ice bath. After the
addition was complete, the mixture was allowed to stir at room
2
5-600 °C using a Mettler Toledo 851 system under a nitrogen
atmosphere.
4
2
Cross-Polarized Optical Microscopy. Neat lanthanide
phytanates were melted between a microscope slide and cover-
slip and then cooled to room temperature. Water added at
the edge of the coverslip was drawn between the two glass
surfaces and surrounded the solidified material by capillary
action. Optical textures were observed with an Olympus IMT-
6
1
temperature for 90 min. After confirming via H NMR that the
product was formed, the reaction was allowed to proceed to
completion overnight. Thereafter, 500 mL of water was added,
followed by powdered sodium bisulfite to quench the oxidation.
The precipitated chromium salts were filtered off using a Buchner
funnel and Whatman no. 4 filter paper, and the solvent was
evaporated. The predominantly acetone mixture that first evapo-
rated was used to wash the chromium salts. The sticky material
obtained after evaporation was suspended in 400 mL of water and
extracted (overnight) into 500 mL of ether, thereby removing
most of the chromium salts. The aqueous layer was washed with
ether several times and added to the product, and the solvent was
evaporated. After workup and distillation, about 20 g of pure
2
cross-polarized optical microscope equipped with a Mettler
FP82HT hot stage and an FP90 programmable temperature
controller.
X-ray Powder Diffraction. XRD patterns were obtained
using the powder diffraction beamline at the Australian Synchro-
tron. Samples were contained within a custom-designed sample
43
stage, mounted on the omega axis of the diffractometer, and
˚
measured in transmission mode. A 1 mm ꢀ 0.8 mm 1 A beam
was aligned to a reference point on the stage containing an
R-alumina standard. X-ray diffraction data from 2 to 82° at
ambient temperature were collected on a Mythen II Microstrip
detector.
1
phytanic acid was collected. The purity was assessed using H
SomeXRDpatternswereobtainedusingaBrukerD8advanced
X-ray diffractometer. Cu KR radiation (40 kV, 40 mA) was
monochromated with a graphite sample monochromator. Each
sample was scanned over the 2θ range of 1-40° with a step size of
NMR and a reversed-phase HPLC/RI detector. NMR spectra
were in accordance with those in the literature and indicated no
significant impurity. HPLC analysis indicated a purity of g95%.
Known impurities of possible side product phytanic ester and
reactant phytanol were ruled out on the basis of the retention
times.
0
.02° and a count time of 4 s/step. Analyses were performed on the
collected XRD data for each sample using Bruker XRD search
match program EVA.
Synthesis of Lanthanide Salts of Phytanic Acid. The
synthesis of the metal soaps was achieved via double decomposi-
Small-Angle X-ray Scattering. SAXS experiments on bulk
Ln phytanates in excess water (Ln = Nd, Sm, Eu, Tb, and Dy)
were carried out at the 15-ID-D (ChemMatCARS) beamline of
2
1
22
tion using the methods of Binnemans et al. and Corkery. The
addition of NaOH to obtain the sodium soap of the fatty acid was
followed by double decomposition with the lanthanide/transi-
tion-metal salt (hexahydrated, either a lanthanide chloride or a
nitrate). Lanthanum, cerium, neodymium, samarium, europium,
gadolinium, terbium, and dysprosium(III) salts were synthesized.
Subsequently, the product was washed with water, ethanol, and
acetone. Thereafter, the dried product was recrystallized from a
pentanol/water (5:1) mixture before the final freeze drying.
FTIR spectroscopy was used to confirm the product formation
as evident from the disappearance of the carbonyl stretch at
44
the Advanced Photon Source (Argonne, Illinois). The experi-
˚
12
ments used a beam of wavelength λ = 1.50 A (8.27 keV) with
dimensions of 200 μm ꢀ 100 μm and a typical flux of 1 ꢀ 10
photons/s. Two-dimensional diffraction images were recorded on
a Bruker 6000 CCD detector with an active area of 94 mm ꢀ 94
mm and a pixel size of 92 μm. The CCD detector was offset from
the main beam, allowing analysis in the q range of 0.0187-0.807
-1
˚
A
at a sample-to-detector distance of 0.6 m. Temperature
control was in the range of 7-90 °C.
For the Ln phytanates where Ln = La, Ce, and Gd, SAXS
experiments were carried out using the SOL beamline at Imperial
College London. X-rays were produced using a Phillips PW2213/
-1
1
700 cm . The final metal soaps usually contained very small
amounts of unreacted phytanic acid.
Elemental Analysis. The carbon and hydrogen contents of
the Ln phytanates (Ln = La, Ce, Nd, Sm, Eu, Gd, Tb, and Dy)
were determined by C/H elemental microanalysis (combustion
analysis) at the University of Otago, New Zealand. The rare earth
metal content was determined using a Varian Vista spectrophot-
ometer with inductively coupled plasma atomic emission
spectroscopy (ICP-AES). Samples for ICP-AES analysis were
prepared by dissolving 0.1 g of Ln phytanate in 1 M HCl (15 mL).
The solution was extracted with diethyl ether (3 ꢀ 30 mL) to
remove the phytanic acid, made up to 100 mL with Milli-Q
water, and used directly for ICP-AES analysis. The phytanic acid
content was determined by analytical HPLC (Alltech Alltime,
2
5
0 generator operating at 40 kV and 30 mA through an AEG-type
0/21 X-ray tube. The X-rays were monochromated using a quartz
crystal monochromator that isolates the Cu radiation, and a line
focus beam was generated. The diffraction pattern therefore does
not consist of a set of concentric circles but instead a series of
symmetrical lines that are detected using an X-ray-sensitive photo-
graphic negative (Kodak, MR). The spacings range of the beam-
line was from approximately 105 to 2 A, enabling both wide- and
small-angle X-ray scattering to be observed.
Experiments on dispersed samples were carried out at the SAXS/
WAXS beamline at the Australian Synchrotron. The experiments
˚
˚
used a beam of wavelength λ = 0.80 A (15.0 keV) with dimensions
2
50 mm ꢀ 4.6 mm ꢀ ID 5 μm).
13
of 700 μm ꢀ 500 μm and a typical flux of 1.2 ꢀ 10 photons/s.
Infrared Spectroscopy. FTIR was performed using a BOMEN
MB 101 from Extech Equipment Pty. Ltd. Spectra of the neat samples
Two-dimensional diffraction images were recorded on a Mar
.
-1
˚
CX165 detector with analysis in the q range of 0.0305-1.047 A
as KBr pellets were obtained at room temperature in the 4000-400
-1
-1
cm range and accumulated for 32 scans at a resolution of 8 cm
.
(
43) Wallwork, K. S.; Kennedy, B. J.; Wang, D. Synchrotron Radiat. Instrum.,
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6
242 DOI: 10.1021/la904006q
Langmuir 2010, 26(9), 6240–6249

Conn et al.
Article
For all samples, image analysis was carried out using AXcess,
an IDL-based software package developed by Dr. Andrew Heron
at Imperial College London.
Table 1. Elemental Analysis of the Ln Phytanates
4
5
phytanic
acid/Ln
a
a
a
Ln
%C
%H
%Ln
(H O)
2 n
Dispersion Procedures. The Ln phytanates (Ln = Eu, Gd,
Tb, and Dy) were dispersed in water to form particles. First, the
lanthanide phytanates were dissolved slowly in the minimum
amount of 2-methyl-2 propanol at 60 °C to form a homogeneous
solution. This was followed by the addition of 10 wt % of stabilizer
Pluronic F127. The mixture of lanthanide phytanate and F127 was
added to 50 mL of Milli-Q water with mixing in an ultratarrax
La
Ce
65.96 (64.95) 10.97 (10.99) 12.9 (11.4) 3.05
65.39 (65.41) 10.86 (10.98) 13.3 (13.0) 2.98
2
1.5
3
2
1
1
1
0
Nd 63.56 (63.61) 10.64 (10.94) 13.4 (11.7) 2.96
Sm 64.12 (64.29) 10.60 (10.88) 13.8 (14.5) 2.93
Eu 65.47 (65.24) 10.78 (10.86) 14.0 (13.5) 2.89
Gd 65.47 (64.93) 10.98 (10.81) 14.4 (14.1) 2.95
Tb 64.64 (64.84) 10.64 (10.79) 14.5 (13.4) 2.85
Dy 66.12 (65.69) 10.90 (10.75) 14.8 (12.6) 2.94
(Polytron PT 10-35 GT, Kinematica, Switzerland) for 5 min at a
speed of 15000 rpm at 80 °C. The dispersion was immediately
passed through a high-pressure homogenizer (Avestin, Germany)
using a pressure of 10 000 psi for six passes at 60 °C.
In addition, the Ln phytanates (Ln = Eu, Gd, Tb, and Dy)
were dissolved in phytantriol at 10 wt % with the addition of
a
The calculated values are given in parentheses.
Luminescent Behavior of Europium(III) Phytanate.
Fluorescence emission spectra for europium(III) phytanate par-
ticle dispersions were measured on a Perkin-Elmer model LS-50B
fluorimeter. Lanthanide ion concentrations were determined as
for the NMR relaxation studies.
CHCl at 60 °C. CHCl was later evaporated off using a rotor
3
3
vapor. This was further dried via a freeze dryer overnight. Five
hundred milligrams of this solution (50 mg of the soap sample)
was dissolved in 49.5 mL of water (containing 5 mg of F127
stabilizer). The mixture was homogenized in an ultratarrax
Molecular Modeling. Avogadro 0.8.1 was used to obtain the
energy-minimum conformation of Gd(III) phytanate (including
one water of hydration) using the Ghemical force field with the
steepest-decent algorithm.
(
Polytron PT 10-35 GT, Kinematica, Switzerland) for 5 min at
a speed of 15000-20000 rpm at 80 °C and immediately passed
through a high-pressure homogenizer (Avestin, Germany) at a
pressure of 10000 psi for four to five passes at 60 °C.
Results and Discussion
Elemental Analysis. The elemental analysis results for C, H,
the lanthanide metals, and the hydration content of the synthe-
sized lanthanide phytanates are shown in Table 1, together with
the molar ratio of phytanic acid and lanthanide metal ions. The C,
H, and lanthanide contents were consistent with the expected
values from the Ln(C19
minimized structure for the molecule Gd(C H COO) (includ-
ing one water of hydration) is shown in Figure 1B. With the
exception of dysprosium phytanate, which is anhydrous, hydra-
tion numbers varied between 1 and 3 water molecules per lantha-
nide phytanate molecule.
All resulting solutions were milky in appearance, indicating the
formation of colloidal particles. The particles were sized by dynamic
light scattering measurement (Coulter LS230 particle size analyzer).
Cryo-TEM. A laboratory-built humidity-controlled vitrifica-
tion system was used to prepare the samples for cryo-TEM. The
humidity was kept close to 80% for all experiments, and the
ambient temperature was 22 °C. A 4 μL aliquot of the sample was
transferred onto a 300-mesh copper grid coated with a lacy
Formvar-carbon film (ProSciTech, Thuringowa, Queensland).
After 30 s of adsorption, the grid was blotted manually using
Whatman 541 filter paper for 2-10 s. The blotting time was
optimized for each sample. The grid was then plunged into liquid
ethane cooled by liquid nitrogen. Frozen grids were stored in
liquid nitrogen until required. The samples were examined using a
Gatan 626 cryoholder (Gatan, Pleasanton, CA) and a Tecnai 12
transmission electron microscope (FEI, Eindhoven, The Nether-
lands) at an operating voltage of 120 kV. At all times, low-dose
procedures were followed using an electron dose of 8-10 elec-
H39COO) stoichiometry. The energy-
3
1
9
39
3
FTIR Spectroscopy. Infrared spectra for the Ln phytanates
Ln = La, Ce, Nd, Sm, Eu, Gd, Tb, and Dy) and for phytanic acid
(
-1
were recorded in the spectral region from 400 to 4000 cm . The
absorption spectral frequencies for phytanic acid, lanthanum(III)
phytanate, and gadolinium(III) phytanate are provided in
Table 2. Because the FTIR spectra for the other lanthanide
phytanates are very similar to that of gadolinium(III) phytanate,
we focus our discussion on this spectrum.
2
˚
trons/A . Images were recorded using a Megaview III CCD
camera and AnalySIS camera control software (Olympus) at
magnifications between 70000 and 110 000ꢀ.
The disappearance of the strong peak corresponding to the
Energy Dispersive X-ray Spectroscopy (EDAX). EDAX
experiments were carried out at the Bio 21 Institute, Melbourne
using a Tecnai T30F TEM fitted with an EDAX detector.
NMR Relaxation and Concentration Dependence Stu-
dies. For particledispersionsofLnphytanates(Ln = Eu, Gd, Tb,
-1
carbonyl stretch at 1710 cm in the IR spectrum indicates the
successful reaction of the metal with phytanic acid. On ionization,
this splits into two peaks at 1600-1500 and 1460-1400 cm
corresponding to the symmetric and antisymmetric vibrations,
-1
- 22
respectively, of COO . In contrast, the absorption maxima
and Dy), the longitudinal and transverse relaxation times, T
, were measured at 20 MHz (0.47 T) and room temperature
with a MINISPEC from Bruker. For T measurements, the stan-
dard inversion-recovery (IR) method was used as the pulse
1
and
corresponding to vibrations within the hydrocarbon chain region
remain almost unchanged upon formation of the soap from the
acid. These include the absorption bands of the C-H stretching
T
2
1
4
6
sequence. The recycle delay time was set to 5 times the T
Typically, 20 points were taken for each T measurement. For T
measurements, the Carr-Pucell-Meiboom-Gill(CPMG) meth-
1
value.
vibrations, viz., the symmetrical stretching vibration of CH
2
at
-1
1
2
2860-2850 cm , the asymmetrical stretching vibrations of CH
2
-1
-1
at 2920 cm and of CH at 2960-2950 cm , and deformation
3
4
6
-
1
od was used. The longitudinal relaxivity, r
relaxivity, r , were then determined from the slope of the linear
regression fits of 1/T and 1/T versus the Gd concentration,
1
, and transverse
bands (twisting and wagging) of CH at 1350-1050 cm
.
3
2
Absorption due to OH stretching modes occurs in the range of
1
2
-1
3500-2500 cm and was observed for gadolinium(III) phyta-
respectively. Todetermine the lanthanideion concentration, 1 mL
of each lanthanide phytanate dispersion was freeze dried and the
lanthanide ion concentration was calculated from the dried mass.
nate as a broad band of medium intensity in this region. This
supports a hydrate structure for gadolinium(III) phytanate or the
4
7
presence of physisorbed water.
Thermal Analysis. DSC measurements were carried out on
all lanthanide phytanates. Samples were heated and cooled at
(
45) 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. London, Ser. A 2006, 364,
635.
46) Modern NMR Techniques for Chemistry Research; Derome, A. E., Ed.;
2
(
(47) Binnemans, K.; Jongen, L.; Bromant, C.; Hinz, D.; Meyer, G. Inorg. Chem.
2000, 39, 5938.
Pergamon Press: Oxford, U.K., 1987; Vol. 6, p 86.
Langmuir 2010, 26(9), 6240–6249
DOI: 10.1021/la904006q 6243

Article
Conn et al.
-
1
Table 2. Infrared Absorption Spectral Frequencies (cm ) with Their Assignments for Phytanic Acid, Lanthanum(III) Phytanate, and
Gadolinium(III) Phytanate
-1
infrared absorption spectral frequencies (cm
La phytanate
)
assignments
O-H stretch
phytanic acid
3600
Gd phytanate
2920
∼2961
∼2864
2927
3340
2
2
926
569
3
340
C-H stretch in CdC-H
a
CH
CH
CH
3
2
2
, C-H asymmetric stretch
, C-H asymmetric stretch
, C-H symmetric stretch
2961
2920
2864
2722
2962
2921
2856
2722
2926
2854
2674
OH stretch
CdO stretch
COO , C-O asymmetric stretch
-
1710
1463
1746 (vw)
1718 (vw)
1
740 (vw)
CH
2
, deformation
1461
1457
1379
1258
1436
1456
1379
1264
1170
-
COO , C-O symmetric stretch
CH , symmetric deformation
progressive bands
CH , twisting and wagging)
3
1379
1297
1226
(
2
1
170
C-O stretch
OH, out-of-plane stretch
CH , rocking
2
COOH, bending mode
COOH, wagging mode
1285
933
735
627
480
933
732
656
935
732
642
a
-1
Broad undefined peak in the region from 3000 to 2900 cm
Table 3. Transition Temperatures of the Ln Phytanates as Deter-
mined by DSC and Cross-Polarized Microscopy
peak at approximately 100 °C is observed for dried dysprosium-
III) phytanate, which elemental analysis had indicated was
(
anhydrous. This suggests that dysprosium(III) phytanate is
hygroscopic.
Ln
T
g
/°C
m
T /°C
La
Ce
-81
-81
-82
-81
-74
72
67-79
47-68
69-73
59-110
67-79
43-80
67-97
71-74
X-ray Diffraction of the Neat Samples. Room-temperature
X-ray powder diffraction images were recorded for the Ln
phytanates (Ln = La, Ce, Nd, Sm, Eu, Gd, Tb, and Dy). The
spectrum for samarium(III) phytanate contained relatively broad
Nd
Sm
Eu
Gd
Tb
Dy
√
√
peaks with d spacings in the ratio of 1:1/ 3:1/ 4 characteristic of
-78
-71
˚
a hexagonal columnar mesophase of lattice parameter 27.7 A
Figure 2A). For all other metal soaps, the spectrum displayed
(
one broad peak roughly coincident with the first-order hexagonal
-1
scan rates of 2.5, 10, and 22.5 °C min in the range of -140 to
90 °C. All of the phytanates showed a glass transition at
reflectionof samarium(III) phytanate. For some of the lanthanide
˚
1
salts, an additional peak at approximately 4.6 A was observed and
approximately -70 to -80 °C (Table 3). Peaks corresponding
to a melting transition were not observed. This probably reflects
both the broad temperature range over which melting occurs
is characteristic of molten hydrocarbon chains within the meso-
phase. We believe that all of the lanthanide phytanates form
self-assembled liquid-crystalline mesophases with molten hydro-
˚
(
as determined by visual observations) and the low enthalpy
carbon chains. Although the peak at 4.6 A was not observed for
change associated with melting for systems that have disordered
hydrocarbon chains. Approximate melting temperatures were
therefore determined by visual observation using optical micro-
scopy (Table 3). No trend is observed with ionic radius. We
compare this with similar data obtained for the same series of
lanthanide oleates where a decrease in the melting point was
observed across the lanthanide series and explained by a con-
sideration of the lanthanide ion size. However, we note that the
highest melting point recorded was for samarium(III) phytanate,
which is the only neat salt to form the hexagonal phase.
all samples, this may be due to the strong X-ray absorption of the
lanthanide(III) ions, which can result in this peak being almost
2
2
flat. A hexagonal columnar phase has previously been observed
for Cu, Zn, Sr, and Ba metal soaps containing a monomethyl-
2
2
branched C16 chain. Again, for these systems, the ability to
form a well-ordered hexagonal mesophase depended on the metal
ion with Ca, Al, Ag, La, Ce, Tb, and Lu metal soaps forming a
more disordered mesophase characterized by a single broad peak
roughly coincident with the first-order hexagonal reflection.
X-ray Diffraction of the Hydrated Samples. SAXS mea-
surements were carried out on lanthanide phytanate samples
following prolonged equilibration in excess water over a period
of approximately 1 month. Note that throughout the text “neat”
refers to a sample without water added and “hydrated” refers
to a sample that has undergone prolonged equilibration in excess
water. SAXS results showed that samarium, europium and
terbium(III) phytanate contain distinct diffraction peaks in
3
4
The thermal behavior of the lanthanide phytanates was also
investigated by TGA. In the TGA trace of air-stored lanthanide
soaps, the dehydration of physisorbed water happens around
1
00 °C. Decomposition to volatiles such as alkanones and CO ,
2
basic soaps, metal oxycarbonates, and metal oxides usually begins
around 200 °C. The TGA traces for the lanthanide phytanates
are, in general, very similar. Dehydration of physisorbed water
occurs between 100 and 150 °C. At 400 °C, a substantial weight
loss of 75-80% is observed for all samples, corresponding to
thermal degradation of the system. We note that a weight loss
√
√
√
the ratio 1:1/ 3:1/ 4:1/ 7, again characteristic of a hexa-
gonal columnar phase; see Figure 2B for terbium(III) phyta-
nate. Neodymium(III) phytanate and dysprosium(III) phytanate
6
244 DOI: 10.1021/la904006q
Langmuir 2010, 26(9), 6240–6249

Conn et al.
Article
Figure 3. (A) Lanthanum(III) phytanate and (B) europium(III)
phytanate in excess water viewed with cross-polarized optical
microscopy recorded at 25 °C. The lanthanum(III) phytanate
sample was viewed 2 weeks after exposure to water.
X-ray powder diffraction images were then recorded for the Ln
phytanates (Ln = La, Ce, Nd, Sm, Eu, and Gd) after longer
equilibration times in water of approximately 6 months. Images
were obtained on the powder diffraction beamline of the Australian
Synchrotron as described in the Experimental Section. For these
samples, cerium, neodymium, samarium, and europium(III) phy-
√
√
tanate contain distinct diffraction peaks in the ratio of 1:1/ 3:1/ 4.
The spectrum for europium(III) phytanate is shown in Figure 2C.
Lanthanum and gadolinium(III) phytanate show two broadened
peaks, one coincident with the first-order hexagonal peak and the
√
√
second coincident with a combined 3 and 4 peak. We suggest
that this represents a hexagonal phase with reduced long-range
order and that very long equilibration times may be required for
hexagonal-phase formation for lanthanum and gadolinium(III)
phytanate.
Figure 1C shows the putative hexagonal columnar structure
formed with Gd ions arranged down the center of the cylinders and
hydrocarbon chains radiating outward. The Gd(III) phytanate
molecules have been rotated around the long axis of the cylinder to
allow the hydrocarbon chains to fill the available space.
Crossed-Polarized Microscopy of Lanthanide Phytanates
in Excess Water. A few small, irregular spherulites were
observed under crossed polarizers for lanthanum, neodymium,
samarium, terbium, and dysprosium(III) phytanate (Figure 3A).
We note that the texture is similar to that seen by Corkery for a
Zn-branched chain soap that also forms a hexagonal columnar
2
2
mesophase, and the result is therefore in agreement with SAXS
and XRD results on hydrated samples. The small overall number
of spherulites observed may reflect kinetic difficulties in forming
the hexagonal mesophase discussed in the following section:
microscopic textures were observed over the course of a week,
and XRD results haveindicated thatthe formation times for some
of the hexagonal mesophases are on the order of months. In fact,
the Zn texture observed by Corkery formed only after 2 years with
the sample having previously displayed a homeotropic texture.
Cerium, europium, and gadolinium(III) phytanate display a
birefringent texture (Figure 3B). Although SAXS and XRD
results indicate that these samples also form hexagonal meso-
phases, relatively short equilibration times necessary for the
microscopy technique used may not have allowed the formation
of this phase.
Figure 2. X-ray diffraction pattern for (A) neat samarium(III)
phytanate obtained using powder XRD (B) terbium(III) phytanate
in excess water via using SAXS and (C) europium(III) phytanate in
excess water via powder XRD. All images were obtained at room
√
temperature. For all samples, diffraction peaks in the ratio 1:1/ 3:1/
√
4
are observed, characteristic of a hexagonal columnar phase.
Hexagonal-Phase Lattice Parameter. The effective lattice
parameter of a hexagonal mesophase was calculated from the
displayed broadened diffraction peaks; however, these were in a
ratio consistent with the formation of a hexagonal phase. The
remaining Ln phytanate samples (Ln = La, Ce, and Gd) displayed
only one broad peak roughly coincident with the first-order
reflection of the more ordered hexagonal phases. It should be
noted, however, that these three samples were run using labora-
tory-based SAXS and a low overall diffraction intensity may have
precluded the identification of higher-order diffraction peaks.
d spacing of the first-order reflection, obtained using XRD and
√
SAXS with the equation a = (2/ 3)d. This is plotted as a function
of the lanthanide(III) ionic radius in Figure 4. We use the ionic
3þ
radii rLn values that are reported in the literature for rare earth
4
8
complexes with a coordination number of 6. Previous research
(48) Shannon, R. D. Acta Crystallogr., Sect. A 1976, A32, 751.
DOI: 10.1021/la904006q 6245
Langmuir 2010, 26(9), 6240–6249

Article
Conn et al.
Table 4. Relaxivities of the Lanthanide Phytanates at 0.47 T
20 MHz) and Room Temperature
(
-
1 -1
particle size (nm) relaxivity (mM
s )
-1
-1
-1 -1
dispersions
D
10
D
50
D
90
r
1
(mM
s
)
r
2
(mM
s )
Eu phytanate 451
Gd phytanate 462
Tb phytanate 458
Dy phytanate 461
Magnevist
626
645
629
639
876
940
882
911
0.04
2.40
0.02
0.11
4.90
0.42
5.45
1.23
2.05
6.26
lanthanum and dysprosium(III) phytanate, such behavior may
reflect the large and small ionic radii of these lanthanides,
respectively, which, for geometric reasons, could prevent the
adoption of the long cylinders associated with the hexagonal
phase. Gadolinium(III) phytanate has a lower-than-expected
d spacing in the absence of water. However, it falls within the
linear trend for d spacing in the presence of water, so the result is
more difficult to explain using geometric arguments.
Figure 4. Plot of HII lattice parameter as a function of ionic radius
for both hydrated and neat samples.
Dispersions of Ln Phytanates. In previous work by us on
lanthanide oleates, we have described the suitability of salts
containing a paramagnetic lanthanide ion (gadolinium(III),
has suggested that the lattice parameter for both well-ordered and
disordered hexagonal mesophases formed by metal soaps with
monomethyl-branched C16 chains displays a linear increase with
dysprosium(III), and terbium(III)) as a contrast agent for mag-
2
2
34,49
increasing ionic radius of the metal ion. Here we also observe an
approximately linear increase in the lattice parameter with ionic
radiusforboth neat and hydratedsamples. A notable exception to
the general trend is neat gadolinium(III) phytanate, which has
netic resonance imaging.
For biomedical applications, such
systems must be dispersed into submicrometer-sized particles for
delivery within the body. We have previously shown that
gadolinium(III) oleate, which forms a gel-like lamellar phase at
room temperature (i.e., with disordered headgroups but chains
locked into an all-trans conformation), may be successfully
˚
an effective hexagonal lattice parameter of approximately 2.5 A
less than that expected from the linear trend. We note that
gadolinium(III) phytanate was resynthesized and the same effec-
tive lattice parameter was obtained in both cases.
3
4
dispersed into submicrometer particles. It may also be incorpo-
rated within a Myverol bicontinuous cubic phase, which not only
results in a dramatically increased relaxivity but also incorporates
favorable properties of the self-assembled phase, such as biocom-
In general, the lattice parameter of the hexagonal mesophases
˚
was found to be in the range 27-31 A. Molecular modeling of the
4
9
structure of the Gd (III) phytanate molecule (shown in Figure 1B)
patibility and the potential for targeted delivery.
indicates that the distance from the Gd headgroup to the end of
the phytanyl chain is approximately 20 A. This suggests signifi-
The formation of a self-assembled hexagonal columnar meso-
phase by several lanthanide phytanates in the presence of water
potentially allows us to directly access these favorable properties
of the self-assembled phase without the requirement of doping.
We have therefore dispersed europium, gadolinium, terbium, and
dysprosium(III) phytanate into submicrometer-sized colloidal
particles using the method described in the Experimental Section.
Additionally, europium, gadolinium, terbium, and dysprosium-
(III) phytanate have been doped within phytantriol cubosomes at
a loading of 10 wt %. The particle size distributions for these
dispersions are given in Tables 4 and 5. Note that for biomedical
applications bulk phases must be dispersed in physiological
buffers. We have previously observed that such buffers can cause
slight structural changes in the dispersed phases of some systems
(unpublished data).
Cryo-TEM Measurements on Dispersed Samples. Cryo-
TEM measurements were conducted on dispersed samples of
europium, gadolinium, terbium, and dysprosium(III) phytanate.
Because of the long equilibration times associated with the
formation of the hexagonal phase in water for these samples,
experiments were run both on freshly prepared dispersions and on
samples that had been allowed to equilibrate in water over a
period of several months before dispersion. We observed no
difference in the dispersed structure of samples prepared using
either of the two preparation methods.
˚
cant chain interdigitation in the hexagonal packing arrangement.
˚
The lattice parameter of the wet samples is 1 to 2 A higher than
those of the neat samples, indicating that these samples swell
slightly in water. Samples are also more likely to form an ordered
hexagonal phase in the presence of water. Although only
samarium(III) phytanate forms a hexagonal phase in the absence
of water, following prolonged equilibration in excess water cerium,
neodymium, samarium, europium, and terbium(III) phytanate
show distinct hexagonal peaks and lanthanum, gadolinium, and
dysprosium(III) phytanate show broadened peaks consistent with
the formation of a less-ordered hexagonal phase. Such behavior is
unlikely to reflect changes in interfacial curvature (addition of
water to the headgroup should reduce the desire for interfacial
curvature with a concomitant decrease in the ease of formation of
the hexagonal phase) and may reflect water stabilization of the
internal cores of the columnar micelles in the hexagonal array.
Note that in the presence of water this phase may also be known as
an “inverse” or “reversed” hexagonal mesophase.
We note that for many samples the lattice parameter obtained
using XRD is higher than that obtained using SAXS and that
more samples displayed distinct hexagonal peaks using XRD.
Because XRD measurements in excess water were run approxi-
mately 5 months after the SAXS measurements, this suggests that
the equilibration times for the formation of an ordered hexagonal
mesophase in excess water are on the order of months.
The dispersed structure of all four samples was similar, con-
sisting mainly of opaque particles and spidery crystals, which
appear black on the TEM images (Figure 5). The opaque particles
were generally spherical, although some faceted particles were
The formation of a well-ordered hexagonal phase is less likely
for lanthanum, gadolinium, and dysprosium(III) phytanate,
which were the only samples not to show distinct hexagonal
diffraction peaks using either powder XRD or SAXS. For
(49) Liu, G.; Conn, C. E.; Drummond, C. J. Langmuir 2009, 10.1021/la902845j.
6
246 DOI: 10.1021/la904006q
Langmuir 2010, 26(9), 6240–6249

Conn et al.
Article
Table 5. Relaxivities of the Lanthanide Phytanates in Phytantriol at
1
0 wt % at 0.47 T (20 MHz) and Room Temperature
-
1 -1
particle size (nm)
relaxivity (mM
s )
-1
-1
-1 -1
dispersions
D
10
D
50
D
90
r
1
(mM
s
)
r
2
(mM
s )
Eu phytanate 461
Gd phytanate 98
Tb phytanate 454
Dy phytanate 447
642
240
616
698
999
449
861
1116
0.534
6.39
0.22
2.33
0.346
5.44
1.79
2.85
observed. A wide size variation was observed from >2 μm down
to 50 nm. This distribution is larger than that calculated using
DLS, suggesting that particles may aggregate with time. In fact,
white precipitated material was visually observed in most sam-
ples. The spidery crystals observed were sometimes, but not
always, associated with the opaque particles. This tended to be
sample-dependent; for europium(III) phytanate, the small crys-
tals observed were not often associated with the opaque particles
(
Figure 5A), whereas gadolinium(III) phytanate particles were
Figure 5. Cryo-TEM images of dispersed samples of (A)
europium(III) phytanate and (B, C) gadolinium(III) phytanate.
often heavily coated (Figure 5B). The opaque particles were very
beam-sensitive, which is common for lanthanide-containing sys-
4
9
the edges. For terbium(III) phytanate-doped systems, we also
observe hexosome-like structures in addition to liposomes and
cubosomes. The dysprosium(III) phytanate-doped system also
contains a mixture of hexosomes and cubosomes. This system
displays a very wide variety of particles sizes with cubosomes
observed up to a micrometer in diameter. In addition, for this
system, many particles have spidery black crystals incorporated
within them (Figure 7B). For all samples, the volume of crystal-
line material observed was much less than that seen for the pure
dispersed phase.
The structure of dispersed phytantriol doped with 10 wt %
europium(III) phytanate differs from that of the other three
samples with no obvious hexosomes, cubosomes, or liposomes.
Rather, we observe opaque, featureless spherical particles that are
mostly <200 nm, similar to those seen in the pure europium(III)
phytanate sample.
tems. However, for some samples some internal structure could
be resolved before beam damage occurred (Figure 5C). It is
therefore possible that such systems retain some order in the
dispersed state. SAXS experiments were carried out on dispersed
samples at the SAXS/WAXS beamline of the Australian Syn-
chrotron with no diffraction peaks resolved. We note that this
does not necessarily indicate the absence of order in the dispersed
systems because the weak scattering intensity associated with
dispersed samples, combined with the highly X-ray absorbing
nature of the lanthanide ions, could preclude peak identification.
The spidery crystals observedare unlikely to be purelanthanide
phytanates, which are noncrystalline even in the nonhydrated
state. However, previous research has shown that gadolinium can
leach out into aqueous solution, and energy-dispersive X-ray
spectroscopy (EDAX) experiments carried out at the Bio21
Institute, Melbourne confirmed the presence of gadolinium in a
sample of the crystalline material (Figure 6). We therefore suggest
that the spidery crystals observed may be insoluble gadolinium
species that have formed in water. Leaching of very toxic free
gadolinium would make these systems unsuitable for biomedical
applications. However, the fact that the particles remain stable in
water for many months and effectively swell very little and do not
undergo a phase change means that any lanthanide leaching must
be relatively small.
Relaxivity Measurements. All of the dispersions described
above were evaluated for their ability to modify the relaxation
rate of protons in vitro using a standard NMR spectrometer at 20
MHz and room temperature. Typical plots to obtain longitudinal
and transverse relaxivities for gadolinium(III) phytanate are
shown in Figure 8. Calculated r and r values for europium,
1
2
gadolinium, terbium, and dysprosium(III) phytanate are pro-
vided in Table 4 along with those for the commercial contrast
agent, Magnevist. Gadolinium-containing systems are positive
contrast agents, meaning that they affect the longitudinal relax-
We have previously shown that the incorporation of
gadolinium(III) oleate within a dispersed bicontinuous cubic
phase increases the relaxivity of the system. We have therefore
incorporated europium, gadolinium, terbium, and dysprosium-
ivity, r . We note that gadolinium(III) phytanate displays a
1
slightly lower longitudinal relaxivity than does Magnevist,
although the transverse relaxivity is similar in both systems. In
contrast, terbium and dysprosium(III) phytanate display relax-
ivity values, both longitudinal and transverse, that are consider-
ably below those of the commercial agent. Europium(III)
phytanate, which is not paramagnetic, has very low relaxivity
values as expected. Although the relaxivity values for gadolinium-
(
III) phytanate at a loading of 10 wt % within phytantriol, which
D
forms a QII bicontinuous cubic phase in excess water at room
temperature. Pure phytantriol may be easily dispersed into
relatively stable, submicrometer cubic-phase particles known as
5
0
cubosomes. Upon addition of 10 wt % Ln phytanate (Ln = Gd,
Tb, and Dy), the dispersed systems consist of a mixture of
cubosomes, hexosomes, liposomes, and/or large irregular faceted
and striated particles (Figure 7A-D, respectively). The doped
systems are more difficult to disperse than pure phytantriol; a
white precipitate was visually observed in most samples, and
particles were “sticky” and often clumped together.
Phytantriol doped with 10 wt % gadolinium(III) phytanate
contains liposomes, large irregularly faceted and striated parti-
cles, and cubosomes with and without bubbles of water around
(
III) phytanate do not show an improvement relative to those of
the commercially available contrast agent, they are of the same
order of magnitude, which when combined with the ability to
form ordered dispersed particles exemplifies the potential of this
type of amphiphilic self-assembly material as a new class of MRI
3þ
contrast agents. We note, however, that Gd toxicity is an
important concern. As discussed in our previous papers on
3
4,49
lanthanide oleates,
it is difficult to make a priori predictions
of the chelation constants for self-assembled lanthanide salts of
long-chain carboxylic acids because reaction equilibria constants
(
50) Dong, Y. D.; Larson, I.; Hanley, T.; Boyd, B. J. Langmuir 2006, 22, 9512.
Langmuir 2010, 26(9), 6240–6249
DOI: 10.1021/la904006q 6247

Article
Conn et al.
Figure 6. EDAX spectrum on a crystal obtained from a dispersion of Gd phytanate.
Figure 7. Cryo-TEM images of dispersed samples of phytantriol
doped with 10 wt % lanthanide phytanate. (A) Cubosome struc-
ture observed within a terbium(III) phytanate-doped sample. (B)
Hexosome structure observed within a dysprosium(III) phytanate-
doped sample. (C) Structured particle of possible hexagonal or
lamellar symmetry observed within a terbium(III) phytanate-
doped sample. (D) Irregularly faceted, striated particle observed
within a gadolinium(III) phytanate-doped sample.
in the interfacial microenvironment of amphiphile self-assembly
5
1
materials can differ considerably from bulk solution values. We
will therefore address the issue of Gd ion toxicity in future work.
Proton relaxivities, r and r , were also determined at 20 MHz
1
2
for phytantriol dispersions containing europium, gadolinium,
terbium, and dysprosium(III) phytanate at 10 wt % and are listed
in Table 5. Incorporation within a cubosome leads to an increase
in longitudinal relaxivity for all samples, and for 10 wt %
gadolinium phytanate in phytantriol, the longitudinal relaxivity
measured is higher than that of the commercial contrast agent. A
similar but more significant increase in relaxivity was observed for
gadolinium oleate incorporated at 10 wt % within Myverol
Figure 8. Plot of proton (a) longitudinal relaxivity r
verse relaxivity r
from Bruker versus the concentration of gadolinium(III) phytanate.
1
and (b) trans-
at 20 MHz and room temperature with a MINISPEC
2
4
9
cubosomes. It has been suggested that incorporation within a
bicontinuous cubic phase, which has both a high surface area and
(
51) Drummond, C. J.; Grieser, F.; Healy, T. W. J. Chem. Soc., Faraday Trans. 1
1
989, 85, 521.
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248 DOI: 10.1021/la904006q
Langmuir 2010, 26(9), 6240–6249

Conn et al.
Article
energy transfer from the excited state to water molecules coordi-
nated to the europium(III) complex. A plot of fluorescence res-
ponse versus europium(III) phytanate concentration (Figure 9B)
shows that, as for europium(III) oleate, the fluorescence response
increases monotonically with europium(III) phytanate concen-
tration, suggesting some potential for this type of amphiphile
self-assembly material in fluorescence imaging.
Conclusions
The current study has demonstrated the feasibility of using
structure-property relationships to induce liquid-crystalline
phase behavior in lanthanide soaps. Here, the introduction of
an isoprenoid-type phytanyl chain induced the formation of a
columnar hexagonal phase in water. We have shown that hex-
agonal-phase formation is dependent on the lanthanide ion
headgroup, being less likely for both smaller and larger ions
presumably because of geometric considerations. The effective
lattice parameter of the hexagonal phase generally increases with
increasing ionic radius of the headgroup in an approximately
linear fashion.
We have successfully dispersed europium, gadolinium, ter-
bium, and dysprosium(III) phytanate into submicrometer parti-
cles. Cryo-TEM results indicate the retention of some order in
these colloidal particles, and relaxivity values calculated for
gadolinium(III) phytanate are comparable to those for the
commercial contrast agent, Magnevist. In addition, a colloidal
dispersion of europium(III) phytanate exhibits the characteristics
of a fluorescence imaging agent exemplifying the potential of this
type of amphiphilic self-assembly material for such applications.
Cryo-TEM results, however, indicate that very toxic free gado-
linium may leach from these systems in water to form insoluble
crystals of gadolinium species, making these exact systems un-
suitable. Because of the potential exhibited by lanthanide oleates
and phytanates, self-assembled amphiphiles with headgroups that
can more strongly chelate lanthanide ions are currently being
investigated.
Figure 9. (A) Fluorescence emission spectrum of a dispersion
of europium(III) phytanate particles in water and (B) the fluores-
cence response curve as a function of europium(III) phytanate
concentration.
Acknowledgment. C.J.D. is the recipient of an Australian
Research Council Federation Fellowship. We thank Dr. Irena
Krodkiewska for the synthesis of gadolinium(III) phytanate,
Sergey Rubanov for assistance with the EDAX experiments,
and Prof. John Seddon and Prof. Richard Templer for the kind
provision of X-ray facilities at Imperial College London. In
addition, we thank Dr. Ben Muir for his critical reading of the
manuscript and Dr. David Cookson and Dr. Robert Knott for
their assistance with experiments carried out at the ChemMat-
CARS beamline, sector 15 at the Advanced Photon Source. Use
of ChemMatCARS sector 15 at the Advanced Photon Source was
supported by the Australian Synchrotron Research Program,
which is funded by the Commonwealth of Australia under the
Major National Research Facilities Program. ChemMatCARS
sector 15 is principally supported by the National Science
Foundation/Department of Energy under grant number CHE-
continuous water networks, may facilitate the coordination of
more water molecules around the paramagnetic ion, increasing
the inner-sphere relaxivity. The cubic phase may also partially
impede the rotational movement of the metal ion, adding to the
increase in the relaxation rate. However, it is noteworthy that
although the disruption of the dispersion order was much
greater for lanthanide oleates incorporated within cubosomes,
4
9
the increase in relaxivity was much higher for these systems.
Luminescence Behavior of Europium(III) Phytanate.
Although nonparamagnetic, europium(III) phytanate exhibits
strong luminescence and has potential in fluorescence imaging.
The emission fluorescence spectrum for a dispersion of europium-
(
III) phytanate (excitation at 300 nm) is shown in Figure 9A. The
spectrum obtained is very close to the typical emission wave-
lengths for europium(III) ions, indicating that the fluorescence
properties of the europium(III) ion have not been quenched on
0535644. Use of the Advanced Photon Source was supported by
the U.S. Department of Energy, Office of Science, Office of Basic
Energy Sciences, under contract no. DE-AC02-06CH11357. Part
of this research was undertaken on the powder diffraction and
SAXS/WAXS beamlines at the Australian Synchrotron, Victoria,
Australia.
3
7,52
dispersion within an aqueous system.
Quenching of fluores-
cence can occur in aqueous systems because of radiationless
(
52) Sinha, A. P. B. Spectrosc. Inorg. Chem. 1971, 2, 255.
Langmuir 2010, 26(9), 6240–6249
DOI: 10.1021/la904006q 6249