Iodinated nanoscale coordination polymers as potential contrast agents for computed tomography

Article abstract of DOI:10.1002/anie.200904958

Nanoscale coordination polymers (NCPs), prepared with metal ions and an iodinated ligand, were synthesized using reverse-phase microemulsion techniques and rapid precipitation procedures. The NCPs carry high payloads of iodine (ca. 63 wt%) and have potent

Full text of DOI:10.1002/anie.200904958

Angewandte
Chemie
DOI: 10.1002/anie.200904958
Coordination Polymers
Iodinated Nanoscale Coordination Polymers as Potential Contrast
Agents for Computed Tomography**
Kathryn E. deKrafft, Zhigang Xie, Guohua Cao, Sylvie Tran, Liqing Ma, Otto Z. Zhou, and
Wenbin Lin*
Computed tomography (CT) is a powerful diagnostic tool
based on X-ray attenuation by a specimen, and is capable of
providing three-dimensional (3D) images with excellent
spatial resolution.[1] A contrast agent with high X-ray
attenuation, typically materials containing elements with a
high Z number such as iodine, barium, and bismuth, is often
used in CT imaging to provide better contrast between the
tissue of interest and its surroundings.[2] The only CT contrast
agents currently approved for clinical use are iodinated
aromatic molecules, and barium sulfate for gastrointestinal
tract imaging. CT imaging with small-molecule contrast
agents is limited by their nonspecific distribution, rapid
renal clearance, and rapid extravasation from blood and
lymphatic vessels.[2] Large doses of small-molecule agents
(tens of grams) are typically needed to provide adequate
contrast, which sometimes cause adverse reactions for the
patients.
late nanoparticles with high loadings for elements having high
Z numbers that are also nontoxic and able to be cleared from
the body in a timely fashion.
Coordination polymers have recently emerged as inter-
esting functional materials that are readily synthesized by
coordination-directed self-assembly of metal ions and organic
bridging ligands.[7] Our research group and others have
recently demonstrated the synthesis of a new class of nano-
materials by scaling down coordination polymers to the nano-
regime.[8] These nanoscale coordination polymers (NCPs)
have already shown great potential in biosensing,[9] magnetic
resonance imaging,[10] and drug delivery.[11] Given the clinical
utility of iodinated aromatic molecules in CT imaging, we
surmised that iodinated NCPs could have potential applica-
tions as CT contrast agents owing to their ability to carry a
very high payload of iodine. Herein we report the synthesis of
new iodinated coordination polymers and their scale down to
the nano-regime. We also demonstrate the ability of iodinated
NCPs to attenuate X-rays in phantom studies.
These limitations can be overcome by nanoparticulate
contrast agents that can carry a high payload and be
functionalized to increase blood circulation times and to
endow target specificity.[3] Nanoparticles do not readily
diffuse into extravascular space or undergo rapid renal
clearance, thus allowing ade-
As shown in Scheme 1, five new coordination polymers
were synthesized using 2,3,5,6-tetraiodo-1,4-benzenedicar-
boxylic acid (I4-BDC-H2) bridging ligands and CuII or ZnII
quate time for accumulation at
a disease site. These advan-
tages could allow for a larger
time window for imaging and
enhanced image contrast at a
lower dose. Several nanoparti-
cle systems including Bi2S3,[4]
gold,[5] and iodinated organic
nanoparticles,[6] have recently
been evaluated as next-gener-
ation CT contrast agents. How-
ever, it is challenging to formu-
Scheme 1. Synthesis of five new coordination polymers.
metal connecting points. The reaction of I4-BDC-H2 and
Cu(NO3)2 in N,N-dimethylformamide (dmf) at 808C for
3 days led to blue rectangular platelike crystals of [Cu(I4-
BDC)(dmf)2] (1) in 28% yield. Similar crystal growth in N,N-
diethylformamide (def) and in H2O led to bluish-green
rodlike crystals of [Cu(I4-BDC)(def)2(H2O) ] (2) in 58%
yield and green rodlike crystals of [Cu(I4-BDC)(H2O)2]·2H2O
(3) in 69% yield, respectively. To demonstrate the generality
of this synthetic approach, we have also synthesized iodinated
coordination polymers with ZnII metal connecting points.
Colorless rodlike crystals of [Zn(I4-BDC)(dmf)2.5] (4) were
obtained in 55% yield by the reaction of I4-BDC-H2 and
Zn(NO3)2 in dmf at 608C for 4 days. Colorless rodlike crystals
of [Zn(I4-BDC)(EtOH)2]·2EtOH (5) were obtained in 28%
[*] K. E. deKrafft, Dr. Z. Xie, S. Tran, Dr. L. Ma, Prof. W. Lin
Department of Chemistry, CB 3290, University of North Carolina
Chapel Hill, NC 27599 (USA)
Fax: (+1)919-962-2388
E-mail: wlin@unc.edu
Homepage: http://www.chem.unc.edu/people/faculty/linw/
wlindex.html
Dr. G. Cao, Prof. O. Z. Zhou
Department of Physics and Astronomy, University of North Carolina
Chapel Hill, NC 27599 (USA)
[**] We acknowledge financial support from the NIH (U54-CA119343)
and the NSF (DMR-0906662).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904958.
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yield by slow evaporation of a solution of I4-BDC-H2 and
(Figure 1d). The adjacent ZnII centers in the zigzag polymeric
chain adopt a tetrahedral geometry by coordinating to two
monodentate carboxylate groups and two def molecules, and
a distorted octahedral geometry by coordinating to one
monodentate and one chelating carboxylate groups and three
def molecules, respectively. Compound 5 has a simpler zigzag
polymeric chain structure with all the ZnII centers adopting
tetrahedral geometry by coordinating to two monodentate
carboxylate groups and two ethanol molecules (Figure 1e).
Importantly, the steric bulk of the iodine atoms forces the
carboxylate groups of the I4-BDC ligand to be perpendicular
to the tetraiodobenzene ring in all of these structures. We
believe that the steric bulk of iodine atoms also discourages
the carboxylate groups of the I4-BDC ligands from adopting
the bridging coordination mode (except in 3), which can lead
to the formation of coordination polymers of higher dimen-
sionality. The thermogravimetric analyses (TGA) of bulk
crystals of 1–5 show solvent and organic weight loss that
corresponds closely to the formulas obtained from X-ray
diffraction data (see the Supporting Information).
Zn(NO3)2 in ethanol. The synthesis of coordination polymers
in H2O and in ethanol (3 and 5) demonstrates the ability to
obtain iodinated coordination polymers that contain nontoxic
solvents, thus making them more relevant for potential
biological and biomedical applications.
Single-crystal X-ray diffraction studies of 1–5 revealed
one-dimensional (1D) polymeric structures for all five
coordination polymers (Figure 1).[12] In compound 1, CuII
ions coordinate to two chelating carboxylate groups of the
We were able to synthesize nanoparticles of both a CuII-
and a ZnII-containing phase, with coordinating H2O and
ethanol molecules, respectively. Platelike nanoparticles of 3
(NCP 3a) were synthesized in 75% yield by stirring a
microemulsion of 0.3 m Triton X-100 and 1.5 m 1-hexanol in
with a water to surfactant ratio of 15 (W value), which
contained equal molar amounts of Na2(I4-BDC) and Cu-
(NO3)2 at room temperature for 2 h. The NCP 3a particles
were isolated by centrifugation and washed with ethanol.
Scanning electron microscopy (SEM) images showed that
platelike particles of NCP 3a have a diameter of 300 nm and
are 50 nm thick (Figure 2a). Powder X-ray diffraction
(PXRD) studies indicate that the NCP 3a particles are
crystalline and have the same structure as the bulk phase of
3 (Figure 2c). Interestingly, nanoparticles of 3 with a rodlike
Figure 1. Single-crystal X-ray structures of 1D coordination polymers of
a) [Cu(I4-BDC)(dmf)2] (1), b) [Cu(I4-BDC)(def)2(H2O)] (2), c) [Cu(I4-
BDC)(H2O)2]·2H2O (3), d) [Zn(I4-BDC)(dmf)2.5] (4), and e) [Zn(I4-
BDC)(EtOH)2]·2EtOH (5). Stick joints: C (light gray), N (medium
gray), O (dark gray); balls: I (light gray), Cu (dark gray). Coordination
around Zn atoms (d,e) are shown as gray polyhedra.
I4-BDC ligand and two molecules of dmf in the axial positions
to form a 1D polymeric network (Figure 1a). In compound 2,
both carboxylate groups of the I4-BDC ligand are mono-
dentate (Figure 1b). The CuII ions adopt a square pyramidal
geometry by coordinating to two monodentate carboxylate
groups as well as one water and two def molecules. The
structure of 3 is ladderlike with one carboxylate group of the
ligand acting in a monodentate fashion, while the other
adopts the h1,m2 bridging mode (Figure 1c). Each CuII center
thus coordinates to three carboxylate oxygen atoms and two
water molecules in a square pyramidal geometry. The distance
between the adjacent I4-BDC ligands in the 1D polymer is
4.06 ꢀ. In compound 4, one I4-BDC ligand has both mono-
dentate carboxylate groups whereas the other I4-BDC ligand
has one monodentate and one chelating carboxylate group
Figure 2. a) SEM images of NCP 3a and b) NCP 3b. c) Simulated
PXRD pattern of 3 (1), and experimental PXRD patterns of bulk
crystals of 3 (2), NCP 3a (3), and NCP 3b (4).
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morphology (NCP 3b) were obtained in 60% yield when the
same reaction was carried out in a microemulsion of 0.1 m
cetyltrimethylammonium bromide and 0.5 m 1-hexanol in
isooctane (W= 15). SEM images show that NCP 3b particles
are about 1.5 mm in length and 200 nm in width (Figure 2b),
and PXRD studies indicate that the particles are crystalline
and also have the same structure as the bulk phase of 3. The
composition of NCP 3a and NCP 3b was also confirmed by
TGA and energy dispersive X-ray spectroscopy (EDS)
results. Slight peak shifts in the PXRD patterns can be
attributed to differences in the temperatures at which data
were acquired and the degree of solvent loss from the sample,
both of which can slightly change the size of the unit cell.
Many of the diffraction peaks are missing in the PXRD
patterns of the NCPs because of the preferential growth along
certain crystallographic faces.
sition of NCP 5a and NCP 5b was also confirmed by TGA
and EDS results.
We conducted phantom studies on NCP 3a and NCP 5b
to evaluate their potential for use as CT contrast agents. Scans
were done on ethanol dispersions with corresponding iodine
concentrations of 0–0.3m (Figures 4a,b).[13] For comparison,
We synthesized microparticles of 5 using a rapid precip-
itation procedure.[11] A dilute aqueous solution of Na2(I4-
BDC) and Zn(NO3)2 in an equal molar ratio was added to
ethanol with rapid stirring. SEM and PXRD studies showed
that the resulting particles (NCP 5a) were crystalline rods
having a less than mm width and were 10–30 mm in length
(Figures 3a,c). We found that smaller particles NCP 5b could
Figure 4. CT phantom images of a) NCP 3a and b) NCP 5b dispersed
in ethanol, and c) Iodixanol in aqueous solution. From the top,
clockwise, the slots have [I]=0, 0.075, 0.150, 0.225, and 0.300m. d) X-
ray attenuation as a function of [I] for NCP 3a at 40 kVp, NCP 5b at
50 kVp, and Iodixanol at 40 kVp.
samples of aqueous solutions of Iodixanol, a clinically used
iodinated contrast agent, were also scanned at the same
iodine concentrations (Figure 4c). Both NCP 3a and NCP 5b
contain 63 wt% of iodine, while Iodixanol contains only
49 wt% iodine.[14] The theoretical iodine payload is 63.2 and
55.3 wt% for NCP 3a and NCP 5b, respectively, based on the
formulas determined by X-ray diffraction data. The higher
than predicted iodine payload for NCP 5b is due to ready loss
of ethanol molecules from the nanoparticles as shown in the
TGA. For comparison, a recently reported polymer-stabilized
lipid nanoparticle contains only 19 wt% iodine in the core,
and iodine loading is even lower when the polymer shell is
taken into consideration.[6a] The Hounsfield unit (HU)[15]
value is an indicator of the ability of a material to attenuate
X-rays with respect to water (0 HU). The slopes of the lines
produced by plotting HU values against iodine concentra-
tions for NCP 3a, NCP 5b, and Iodixanol are (4653 Æ 520),
(4513 Æ 408), and (3840 Æ 560) HU/M, respectively (Fig-
ure 4d). The nanoparticles thus show X-ray attenuation
coefficients comparable to that of the molecular contrast
agent. The slightly higher X-ray attenuation of the NCPs can
be attributed to the contribution from Cu and Zn, calculated
to be approximately 5% based on the weight% of these
Figure 3. a) SEM images of NCP 5a and b) NCP 5b. c) Simulated
PXRD pattern of 5 (1), and experimental PXRD patterns of bulk
crystals of 5 (2), NCP 5a (3), and NCP 5b (4).
be obtained by addition of a more concentrated aqueous
precursor solution (pH 6.6) to ethanol. The resulting white
cloudy dispersion was stirred at room temperature for 1 hour.
The NCP 5b nanoparticles were isolated in 82% yield by
centrifugation and washed with ethanol. SEM images show
that the NCP 5b particles have a truncated cube morphology
with a diameter of 200–600 nm (Figure 3b). PXRD studies
show that they match the bulk phase of 5 (Figure 3c), but the
very broad peak indicates a large degree of disorder in the
structure of these partially crystalline particles. The compo-
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metals in the materials and the attenuation of the metals
compared to that of iodine.
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The biodegradable nature of NCPs makes them attractive
candidates for imaging applications, because it is important
that a diagnostic agent be cleared from the body after
use.[8a,10b] To determine the dissolution (degradation) behav-
ior of the iodinated NCPs in a biologically relevant environ-
ment, we dialyzed NCP 3a against phosphate buffered saline
(PBS; pH 7.4) at 378C. The particles were completely
dissolved after approximately 46 hours, with a half-life of
about 1.5 hours (Figure S10 in the Supporting Information).
This result demonstrates the biodegradable nature of the
NCPs while they are still stable enough to allow for longer
circulation time as compared to molecular iodinated contrast
agents (< 10 min).
In summary, we have synthesized novel iodinated coordi-
nation polymers as well as corresponding nanoparticle phases
with controllable morphologies and demonstrated their
potential for CT contrast enhancement. These new nano-
materials are capable of delivering high payloads of iodine
and offer a new strategy for designing efficient CT contrast
agents that do not suffer from the inherent drawbacks of
small-molecule agents.
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129, 9852.
Experimental Section
A typical procedure for crystal growth: 1 was synthesized by
dissolving I4-BDC-H2 (4.02 mg, 6.00 mmol) and Cu(NO3)2·3H2O
(1.45 mg, 6.00 mmol) in a mixture of dmf (670 mL) and H2O (34 mL)
with HCl (1 equiv, 6.00 mmol). The vial containing the resulting clear
solution was capped and placed in an 808C oven. After 3 days blue,
rectangular plate-shaped crystals were obtained in a yield of 1.46 mg
(27.7%).
[10] a) W. J. Rieter, K. M. L. Taylor, H. An, W. Lin, W. J. Lin, J. Am.
Chem. Soc. 2006, 128, 9024; b) K. M. L. Taylor, W. J. Rieter, W.
Lin, J. Am. Chem. Soc. 2008, 130, 14358.
Synthesis of NCP 3a: Two microemulsions with W= 15 were
prepared by the addition of 1.215 mL of an aqueous solution of I4-
BDC sodium salt (0.1m, pH 9.6) and 1.215 mL of a 0.1m Cu(NO3)2
aqueous solution to separate 15 mL aliquots of a 0.3m Triton X-100
and 1.5m 1-hexanolin cyclohexane. The separate microemulsions
were stirred vigorously for 10 min at RT before the two micro-
emulsions were combined, and the resultant 30 mL microemulsion
with W= 15 was stirred for an additional 2 h at RT. The nanoparticles
were isolated by centrifugation at 13000 rpm for 10 min. After the
removal of the supernatant the particles were washed twice using
10 mL of ethanol each time. For each wash, the particles were
redispersed by sonication and then recovered by centrifugation at
13000 rpm for 10 min to give a yield of 69.9 mg (75.0%).
Synthesis of NCP 5b: A 200 mL aqueous precursor solution of
0.05m Na2(I4-BDC) and 0.05m Zn(NO3)2 was prepared and its pH was
adjusted to 6.6 with NaOH. This precursor solution was quickly
transferred into 25 mL of ethanol in a 50 mL round bottom flask with
rapid stirring. This resulted in the immediate formation of a white
cloudy dispersion, which was stirred at RT for 1 h. The product was
isolated and washed as described above for NCP 3a to give a yield of
6.35 mg (81.5%).
[11] W. J. Rieter, K. M. Pott, K. M. L. Taylor, W. Lin, J. Am. Chem.
Soc. 2008, 130, 11584.
[12] Single-crystal X-ray diffraction data were measured on a Bruker
SMART Apex II CCD-based X-ray diffractometer system
equipped with a Cu-target X-ray tube (l = 1.54178 ꢀ). Crystal
data for 1: Orthorhombic, space group: CmcC21, a = 10.928(1),
b = 21.668(2),
c = 9.579(1) ꢀ,
V= 2268.1(3) ꢀ3,
1calc =
2.569 gcmÀ3. Crystal data for 2: Monoclinic, space group: P21,
a = 11.175(1), b = 10.114(1), c = 12.246(1) ꢀ, b = 107.293(2)8,
V= 1321.5(1) ꢀ3, 1calc = 2.386 gcmÀ3. Crystal data for 3: Mono-
clinic, space group: P21/c, a = 11.020(1), b = 9.690(1), c = 15.937
(1) ꢀ, b = 105.164(5)8, V= 1642.5(2) ꢀ3, 1calc = 3.248 gcmÀ3
.
Crystal data for 4: Orthorhombic, space group: P212121, a =
10.387(1), b = 11.758(1), c = 38.819(2) ꢀ, V= 4740.9(3) ꢀ3,
1calc = 2.566 gcmÀ3
.
Crystal data for 5: Monoclinic, space
group: C2/c, a = 11.433(1), b = 14.879(1), c = 15.438(1) ꢀ, b =
95.718(1)8,
V= 2613.16(9) ꢀ3, 1calc = 2.327 gcmÀ3
.
CCDC 744845, 745368, 744106, 744846, and 744107 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] G. Cao, Y. Z. Lee, R. Peng, Z. Liu, R. Rajaram, X. Calderon-
Colon, L. An, P. Wang, T. Phan, S. Sultana, D. S. Lalush, J. P. Lu,
O. Zhou, Phys. Med. Biol. 2009, 54, 2323.
Received: September 3, 2009
Revised: October 25, 2009
Published online: November 24, 2009
[14] The amount of iodine that can be incorporated in small-molecule
agents is limited by the need for side chains that increase
hydrophilicity and decrease osmolality, viscosity, and toxicity.
[15] R. A. Brooks, J. Comput. Assist. Tomo. 1977, 1, 487.
Keywords: computed tomography · contrast agents ·
coordination polymers · iodine · nanoparticles
.
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