A structural and 1H NMR relaxometric study on novel layered carboxyalkylaminophosphonate nanocrystals with Gd(iii) ions located in the framework

Article abstract of DOI:10.1039/c5dt02808f

Novel Gd(iii) carboxyalkylphosphonate nanocrystals were synthesized under mild hydrothermal conditions. Structural properties and ¹H NMR relaxometric behaviour in aqueous solution as a function of the magnetic field strength were investigated, aiming to evaluate the local chemical environment of the paramagnetic centres and their interaction and affinity with water molecules.

Full text of DOI:10.1039/c5dt02808f

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COMMUNICATION
1
A structural and H NMR relaxometric study on
novel layered carboxyalkylaminophosphonate
nanocrystals with Gd(III) ions located in the
framework†
Cite this: DOI: 10.1039/c5dt02808f
Received 23rd July 2015,
Accepted 12th October 2015
DOI: 10.1039/c5dt02808f
a
b
c
c
c
Antonio Scafuri, Riccardo Vivani, Fabio Carniato, Lorenzo Tei, Mauro Botta,*
d
a
www.rsc.org/dalton
Marco Taddei and Ferdinando Costantino*
Novel Gd(III) carboxyalkylphosphonate nanocrystals were syn- also examined by relaxometric techniques and proposed as
1
6,17
thesized under mild hydrothermal conditions. Structural properties potential T
and H NMR relaxometric behaviour in aqueous solution as a func-
1
and T
2
MRI contrast agents.
1
However, despite the many examples reported in the litera-
tion of the magnetic field strength were investigated, aiming to ture, the direct synthesis of nanosized materials containing Gd
evaluate the local chemical environment of the paramagnetic (III), using low cost and facile one-pot procedures, remains an
centres and their interaction and affinity with water molecules.
ambitious yet not fulfilled goal. Lanthanide phosphonates
have been extensively studied during the last few years owing
to their facile synthesis and high structural versatility.
Over the last decade, several inorganic and hybrid organic/
inorganic nanoparticles (NPs) functionalized with paramagnetic
18
Phosphonic groups display good affinity towards Ln(III) ions
giving rise to highly insoluble compounds. In addition, an
appropriate choice of the molecular geometry of the building
block could allow the presence of free functional groups,
which serve as anchoring groups or for bio-conjugation.
In light of these considerations, a new family of layered
1
–3
ions (both transition metals and f elements)
or with metal
4
–6
chelates have been designed and employed for a number of
applications, especially in diagnostics and bioimaging. Zeo-
lites activated with lanthanide ions (Gd(III) and Eu(III)) have
been considered for magnetic resonance, optical and/or multi-
modal imaging applications. Mesoporous silica nanoparticles
containing Gd(III) ions in the inorganic framework or function-
7
3+
carboxyalkyl-phosphonate NPs containing paramagnetic Gd
8
ions as framework metals has been prepared and character-
ized in this work. In this regard, phosphonates/phosphinates
are known to be stable compounds and they have been largely
employed as stable chelators. As an example, Gd phosphate
based nanoparticles have been recently employed as contrast
agents (CAs) in MR imaging both self-standing and conjugated
alized on the external surface with highly stable Gd(III)-
9
–12
chelates
and Ln
number of biomedical applications.
have been thoroughly investigated. LnF
3 4
/NaLnF
2 3
O NPs are being actively studied and used in a
1
3
Recently, detailed
studies were carried out to elucidate the mechanisms under-
lying their interaction with water molecules and the role of the
19
with DNA single strands. Among phosphonates, amino-
14,15
surface in determining their relaxometric properties.
More
bis(methylenephosphonates) possess an affinity towards lantha-
recently, Gd(III)-based metal organic frameworks (MOFs) were
20
nide ions comparable to other ligands. In a recent paper,
carboxyalkylamino-N,N-bis(methylphosphonates) were used as
a
ligands by some of us for the synthesis of layered Ln(III) deriva-
Department of Chemistry, Biology and Biotechnologies, University of Perugia,
2
1
tives (with Ln = Eu, Tb, Er, Yb). The synthetic conditions and
the high insolubility of these compounds allowed us to obtain
stable aqueous dispersions of elongated Ln(III) phosphonate
nanoparticles with the size ranging from 200 to 500 nm.
In this communication we report on the synthesis and
characterization of three novel Gd(III) carboxyphosphonates,
obtained by the reaction of Gd(NO ) with N-phosphono-
Via Elce di Sotto 8, 06123 Perugia, Italy. E-mail: ferdinando.costantino@unipg.it
b
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1,
0
c
6123 Perugia, Italy
Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte
Orientale “Amedeo Avogadro”, Viale T. Michel 11, 15121 Alessandria, Italy.
E-mail: mauro.botta@uniupo.it
d
Laboratory for Catalysis and Sustainable Chemistry, Paul Scherrer Institut,
5
†
232 Villigen PSI, Switzerland
Electronic supplementary information (ESI) available: Instrumental details,
3
3
1
methylglycine (hereafter H L ), 4-(bis(phosphonomethyl)-
3
synthetic procedures, supplementary TEM and structural figures, thermo-
2
amino)butanoic (hereafter
methyl)amino)caproic (hereafter H L ) acids under mild
5
H L ) and 6-(bis(phosphono-
gravimetric data, complete crystallographic data for 1 and 3. CCDC 1415039,
3
1
415040. For ESI and crystallographic data in CIF or other electronic format see
5
DOI: 10.1039/c5dt02808f
hydrothermal conditions. The molecular structures of the
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towards the N-atom of the amino group of the adjacent glycine
moiety (P18–O20⋯N3 = 2.85 Å), suggesting that a non-covalent
interaction exists between these two atoms, or better, that the
nitrogen is protonated by the neighboring PO-H group (Fig. S2†).
The structure of compound 2 was not solved because the
crystallinity of the compound was too low, and the indexing
process was unsuccessful. However, the diffraction pattern of
this phase was similar to that of compound 3 with a strong
basal peak at a low 2θ angle, which can be ascribed to the layer
stacking (Fig. S3†). The d-spacing is about 14.4 Å, which is
compatible with an interdigitated arrangement of the butanoic
chains, in agreement with what is observed for compound 3 (con-
taining hexanoic chains) with a basal distance of about 18 Å.
Compound 3 shows a layered structure with layers com-
Scheme 1 Molecular structure of the three polydentate phosphonate
ligands.
9 3
posed of both GdO distorted tetragonal antiprism and PO C
tetrahedra, belonging to the diphosphonic moieties. The Gd
ion is directly bound to a water molecule. The inorganic layers
three carboxyalkylaminophosphonic acids are shown in the are constituted of a corrugated plane of nine-coordinate Gd
Scheme 1.
ions with a distorted tetragonal antiprism coordination. The
1
A comparison of the structural and H NMR relaxometric be- average Gd–O distances were in the range 2.2–2.8 Å with two
havior in aqueous solution of all of the samples was undertaken, long bond distances of about 2.6 to 2.8 Å (Gd–O2 = 2.8 Å and
aiming to evaluate the chemical environment of the paramag- Gd–O4 = 2.6 Å). The Gd–Ow distance (Ow = water molecule) is
netic ions and their interaction/affinity with water molecules.
The reaction of Gd(NO with the three ligands in aqueous oxygen atoms of the two phosphonic moieties, above and
solution led to the formation of layered Gd(III) phosphonate below the plane of the layer. One PO C tetrahedron is internal
about 2.25 Å. These polyhedra are connected through the
3 3
)
3
1
2
materials with the formula Gd(HL ) ,(1), Gd(H O)(H L ), (2) to the sheet (P8) and it is connected to four different Gd(III)
2
2
2
3
and Gd(H
nates were solved ab initio from powder X-ray diffraction only to one Gd(III). The carboxyalkyl chains are placed into the
PXRD) data and fully characterised by Fourier transform infra- interlayer region in an interdigitated disposition. The chains
red (FT-IR) spectroscopy, thermogravimetric analysis (TGA) are in a bent conformation because one oxygen atom of the
and transmission electron microscopy (TEM).
carboxylic group (O19) is involved in a H-bond with the free
Compound 1 has a layered structure, in which the layers are oxygen atom of the phosphonic group (O5) belonging to the in-
composed of PO C tetrahedra and GdO coordination poly- organic layer, with distance P8–O5⋯O19 = 2.5 Å (Fig. S4†).
2 2
O)(H L ) (3). The structures of two of these phospho- ions. The other phosphonate tetrahedron (P7) is connected
(
3
7
hedra. The aminocarboxylic chains point towards the interlayer
The structures of compounds 1 and 3 are shown in Fig. 1.
space; the layer was formed by the interconnection between
Thermogravimetric curves are shown in Fig. S5.† Com-
the Gd(III) ions (showed as violet atoms) and phosphonate pound 1 possesses high thermal stability (up to 300 °C) and
ligands: one gadolinium ion joins six oxygen atoms coming no structural water molecules are present, in agreement with
from five different phosphonate tetrahedra and one carboxylic the X-ray structure. Compound 2 shows a neat weight loss of
oxygen belonging to the adjacent glycine chain. The coordi- about 2% below 200 °C that is compatible with one Gd co-
nation of the COO− groups to the Gd(III) was also proved by ordinated water molecule. Compound 3 also shows a neat
recording the FT-IR spectrum of sample 1 that shows a band weight loss of about 3% at 150 °C corresponding to the evapor-
at 1610 cm− (asymmetric stretching of the COO ) that falls at ation of one Gd-coordinated water molecule. In agreement
1
−
lower frequencies when compared to the typical absorption of with the crystal structure, no intercalated water is present.
free carboxylate groups (Fig. S15†). For comparison the FT-IR
Stable dispersions of compounds 1–3 have been obtained at
4
L is also reported in Fig. S16.† The asym- neutral pH by slowly adding 0.1 M NaOH that favours the dis-
1
spectrum of pure H
−
1
metric stretching of carboxylate falls at 1732 cm , which is persion of the particles by acid–base interactions and then the
typical of uncoordinated carboxylic groups. The organic moi- pH was adjusted to 7 with HCl. The dispersions are stable over
eties are exposed from the inorganic framework, occupying several days as shown in Fig. S9.† The samples, before and
the region among the layers. In this compound, the Gd(III) after sonication in water suspension, were examined by field
coordination sphere does not contain water molecules, as also emission scanning (FE-SEM) and transmission electron
confirmed by TGA analysis. Furthermore, there is a network of microscopy (TEM), respectively. The micrographs are reported
H-bonds involving the carboxylate groups and the free P–O in Fig. 2. The crystal morphology of the three samples reflects
group. One of the carboxylic oxygen atoms (O15) strongly inter- their layered structure, as they are flat elongated platelet crys-
acts, via H-bond, with the oxygen atom of the phosphonic tals with prismatic shape. In the FE-SEM images (Fig. 2a, c
group belonging to the adjacent layer (see Fig. S1†). Another O and e), the nanocrystals are close to each other, forming aggre-
atom of the doubly connected phosphonic group points gates of a few microns. After sonication, the nanocrystals
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Table 1
1
r values (per Gd) measured at 0.47 and 1.41 T (298 K)
(mM− s−1
1
)
r
(mM−1 s−1
)
r
1
1
2 1
r /r
0.47 T
1.41 T
0.47 T
1
2
3
3.9
1.4
0.6
4.7
1.7
0.6
1.2
1.7
2.8
1
The H NMR relaxometric behaviour of the three com-
pounds in aqueous suspension was investigated at 298 K and
1 2
at neutral pH. The longitudinal (r ) and transverse (r ) proton
relaxivities represent key parameters that describe the efficacy
of the paramagnetic ion in increasing the nuclear magnetic
relaxation rates of the water protons, normalised to a concen-
tration of 1 mM. The r
1
values at 0.47 and 1.41 T are reported
in Table 1. The r /r values at 0.47 T (Table 1) are low
2
1
(
especially for samples 1 and 2), thus indicating that such
materials behave as positive MRI contrast agents.
The r1 enhancement stems from the dipolar coupling
between the proton nuclei of the water molecules and the
metal ions, which involves two basic mechanisms: a short-
range interaction with either metal-bound water molecules
(inner sphere contribution, IS) or H-bonded to polar groups of
the ligand (SS contribution) and a long-range interaction with
water molecules of the bulk diffusing next to the surface (outer
sphere contribution, OS). The magnetic coupling with the
water protons in many inorganic NPs has a marked depen-
dence on the position of the Gd(III) ions within the particle.
The ions located in the core of the particle may contribute to
Fig. 1 Polyhedral representation of the structure and coordination
environment of Gd of 1 (a and b, respectively) and 3 (c and d, respect-
ively). Gd polyhedra are represented in light violet, PO
represented in green.
3
C tetrahedra are
1
r mainly through the OS mechanism, which gradually
becomes less important with the increase of their distance
from the surface. The ions on the surface, instead, contribute
through the SS mechanism and, in the case of coordinated
waters, also through the IS mechanism. Therefore, the calcu-
lated value of the ionic relaxivity (per Gd) represents only an
average value between limit situations characterized by quite
different contributions. However, a similar result may occur
when the water molecules have free access to the inside of the
sample, but their rate of diffusion, and hence exchange with
the bulk, is slow.
1
The H relaxivity as a function of the proton Larmor fre-
22
quency (Nuclear Magnetic Resonance Dispersion, NMRD) was
measured at 298 K over the range 0.01–70 MHz. The NMRD
profile of 3 is characterized by low r values over the entire fre-
1
quency range to indicate that only the OS mechanism is operat-
ive. As already noted above, the low r values reflect an average
1
between the ions closer to the surface whose interaction with
the solvent is relatively strong and the ions embedded in the
nanoparticle that do not contribute at all to the observed relax-
ivity. A fit of the data to the OS relaxation theory provides an
effective distance of closest approach of 9.7 Å for the outer-
Fig. 2 FE-SEM (left) and TEM (right) images of 1 (a, b); 2 (c, d); 3 (e, f)
nanocrystals.
appeared better separated and they have an average size of sphere water molecules with a standard value for the diffusion
about 100 to 200 nm measured along the short axis and up to coefficient of 2.3 × 10− cm s at 298 K.
5
2
−1
23
6
00–700 nm measured along the elongation axis (Fig. 2b, d
On the other hand, the NMRD profiles of 1 and 2 are charac-
terized by a low frequency plateau (0.01–2 MHz) and a broad
and f).
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1
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8
9
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SS
SS
Gd ( q = 1 for 1 and q = 0.3 for 2) at an average distance, r,
of 3.5 Å and with a SSτ
value of 275 and 240 ps for 1 and 2,
R
1
1
1
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1
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by a layered structure containing Gd(III) ions located in the
layers with different coordination spheres. The relaxation pro-
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chains and therefore on the hydrophilic/hydrophobic character
of the chemical environment of the paramagnetic site that
determines its interaction with water. In fact, compound 1,
with a glycine moiety and thus higher hydrophilicity, displays
the best relaxometric performances, owing to its strongest SS
contribution, in good agreement with the crystal structure. It
is worth noting that the relaxivity of 1 (per Gd) is quite similar
to that of the clinically used MRI probes.
1
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1
An appropriate selection of the precursors used in the Ln-
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modulation of the physico-chemical and relaxometric pro-
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2
2
2
2
2 M. Botta, Eur. J. Inorg. Chem., 2000, 399.
Acknowledgements
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F. C., A. S., M. T., and R. V. thank project FIRB 2010 no.
RBFR10CWDA_003 for the financial support.
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