Crystal structure dependent in vitro antioxidant activity of biocompatible calcium gallate MOFs

Article abstract of DOI:10.1039/C6TB03101C

Two novel 3-D coordination polymers, denoted MIL-155 and MIL-156 (MIL stands for Materials Institute Lavoisier), built up from calcium and the naturally occurring gallic acid (H₄gal), have been hydrothermally synthesized and their crystal struc

Full text of DOI:10.1039/C6TB03101C

Journal of
Materials Chemistry B
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Crystal structure dependent in vitro antioxidant
activity of biocompatible calcium gallate MOFs†
Cite this:DOI: 10.1039/c6tb03101c
a
a
a
b
Tania Hidalgo,‡ Lucy Cooper,‡ Martin Gorman, Tamara Lozano-Fernandez,
´
b
a
a
Rosana Simon-Vazquez, Georges Mouchaham, Jerome Marrot,
Nathalie Guillou, Christian Serre,§ Pierre Fertey, A´ frica Gonzalez-Fernandez,
Thomas Devic¶* and Patricia Horcajada 8*
´
´
´
a
a
c
b
´
´
a
a
Two novel 3-D coordination polymers, denoted MIL-155 and MIL-156 (MIL stands for Materials Institute
Lavoisier), built up from calcium and the naturally occurring gallic acid (H gal), have been hydrothermally
synthesized and their crystal structures were determined by single-crystal X-ray diffraction. These solids
are based on different inorganic subunits: infinite chains of edge-sharing dimers of CaO polyhedra linked
gal) O, and
]ꢁ2H
ribbon-like inorganic subunits containing both eight-fold or six-fold coordinated Ca ions linked through
4
7
2
ꢀ
through partially deprotonated gallate ligands (H
2
gal ) for MIL-155 or [Ca
2
(H
2
O)(H
2
2
2
II
4
ꢀ
fully deprotonated gallate ligands (gal ) for MIL-156 or [Ca
contain small channels filled with water molecules, with, however no accessible porosity towards N
7 K. MIL-155 and MIL-156 were proven to be biocompatible, as evidenced by in vitro assays (viability
3
K
2
(H
2
O)
2
(gal)
2
]ꢁnH
2
O (n B 5). Both solids
Received 29th November 2016,
Accepted 14th March 2017
2
at
7
and cell proliferation/death balance). While the high chemical stability of MIL-156 makes it almost
bioinert, the progressive degradation of MIL-155 leads to an important protective antioxidant effect,
associated with the release of the bioactive gallate ligand.
DOI: 10.1039/c6tb03101c
rsc.li/materials-b
Besides conventional applications in the fields of fluid storage/
separation or catalysis, bio-related properties have recently
Introduction
4–6
Over the past twenty years, porous coordination polymers attracted much attention. While MOFs were initially considered
7
(
PCPs) or metal organic frameworks (MOFs) have been widely as carriers for the delivery of diverse active ingredients (AIs),
studied with regard to various potential applications, mostly other areas of application have also emerged, such as bio-
1
–3
8
9,10
11
associated with the sorption properties of these materials.
imaging, sensing
or enzyme immobilization. Although
the traditional use of MOFs as drug carriers is based on the
adsorption/desorption of the AIs within the MOF porosity,
the incorporation of the AIs as a constitutive part of the hybrid
a
Institut Lavoisier, UMR 8180 CNRS Universit ´e de Versailles Saint-Quentin-en-Yvelines,
5 avenue des Etats-Unis, 78035 Versailles cedex, France.
4
1
2–16
framework has recently attracted great attention.
This
E-mail: thomas.devic@cnrs-imn.fr
b
Immunology, Biomedical Research Center (CINBIO) and Institute of Biomedical
Research of Vigo (IBIV), Universidad de Vigo, Campus Lagoas Marcosende,
latest strategy allows not only to tune the release of the AI
through the degradation of the network, which strongly
depends on the metal/ligand pair and the structure, but also avoids
the possible toxicity inherent to the exogenous compounds (i.e.
cations or ligands), typically used for the MOF synthesis. Therefore,
3
6310 Vigo, Pontevedra, Spain
c
Synchrotron Soleil, beamline Cristal, L’Orme des Merisiers, Saint-Aubin,
1192 Gif-sur-Yvette cedex, France
Electronic supplementary information (ESI) available: Experimental data
9
†
including detailed synthetic procedures, characterization (XRD, IR spectra, it is generally accepted that the combination of abundant endo-
crystallography data, bond valence calculations) for both MOFs as well as the
genous cations (M = Zn, Fe, Mg, Ca,...) and naturally occurring
ligands, using non-toxic solvents, is an appealing strategy to
achieve more sustainable biofriendly materials.
ROS production, annexin and cytotoxicity assays of each one and their precursor.
CCDC 1519913 and 1519914. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c6tb03101c
17
Calcium is a particularly advantageous candidate for biomedical
Current address: Institut des Mat ´e riaux Poreux de Paris, FRE 2000 CNRS Ecole applications due to its low cost and abundant presence in the body
‡
§
These authors contributed equally to this work.
Normale Sup ´e rieure – Ecole Sup ´e rieure de Physique et de Chimie Industrielles de
(
B1 kg in the average human body) together with its high recom-
Paris, Paris Research University, Paris, France.
18,19
mended intake (B1 g per day).
In particular, calcium is involved
¶
Current address: Institut des Mat ´e riaux Jean Rouxel, UMR 6502 CNRS Uni-
versit ´e de Nantes, 2 rue de la Houssini `e re, 44322 Nantes cedex 3, France.
Current address: IMDEA Energy. Av. Ram o´ n de la Sagra 3, 28935 M o´ stoles,
in bone health and other important physiological processes such as
enzyme activation, nerve impulse transmission, hypertension,
8
2
0–22
Madrid, Spain. E-mail: patricia.horcajada@imdea.org
obesity modulation and muscle contraction, among others.
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Amongst the large panel of biologically occurring or bioactive phorbol 12-myristate-13-acetate (PMA) was provided by Abcam
2
3
molecules potentially used as ligands (nucleobases,
Biochemicals, H
2
O
2
(30% w/v) by Panreac (Barcelona, Spain),
24–26
27
28
0
0
carboxylates,
phenolic derivatives
their natural abundance and their known antioxidant activity.
In particular, gallic acid (H gal) is an abundant naturally occurring were used as received without further purification.
carbohydrates, amino acids, small peptides ), 2 ,7 -dichlorofluorescein diacetate (2.5 mM; DCFH-DA) by
29,30
also appear to be suitable spacers due to Invitrogent and the Annexin V-FITC Apoptosis Detection Kit
3
1,32
was supplied by Immunostep (Salamanca, Spain). All materials
4
hydroxycarboxylic acid with interesting antioxidant properties,
associated with various beneficial therapeutic effects, including
Synthesis
3
3
34
anti-allergic, -inflammatory, -viral, -fungal, -microbial and
Crystals suitable for single crystal X-ray diffraction analysis
were synthesised hydrothermally at 120 1C, although MIL-155
could also be synthesised under reflux as a microcrystalline
powder.
3
5,36
37
38
even -carcinogenic,
activities.
as well as cardio and neuro-protective
However, to the best of our knowledge, while several 1-D
IV
coordination polymers built up from this ligand and Zr have
MIL-155: [Ca
2
(H
2
O)(H
2
gal)
2
]ꢁ2H
2
O. Gallic acid monohydrate
3
9,40
been structurally characterized,
-D metal (M) gallate has been reported so far. It consists of
infinite chains of corner-sharing MO octahedra connected
through gallate ligands to define triangular shaped channels.
only one structure type of
(0.376 g, 2 mmol) was dissolved in distilled water (10 mL) at
3
room temperature. Calcium nitrate (0.236 g, 1 mmol) was then
added to the solution followed by a KOH 5 M aqueous solution
which was added dropwise until the solution reached pH B 8/9
6
III
II
II
This solid can be prepared from various cations (Fe , Co , Ni ,
(B800 mL = B4 mmol).
II
II
II
Mn or Mg ) and is formulated as Fe(galH)ꢁ2H O or M (galH )ꢁ
2
2
The reaction mixture was then sealed in a Teflon lined
4
1–43
II
2
H O.
2
We recently showed that the Mg analogue combines
autoclave reactor, placed in an oven, heated up to 120 1C in
h, and then kept at this temperature for 12 h; the final pH
an accessible microporosity together with a high biocompatible
character and a strong antioxidant activity for promyelocytic
1
value was 8. Once cooled to room temperature the resulting
crystalline powder was filtered, repeatedly washed with distilled
water and dried at room temperature. This solid could also be
synthesised under reflux on a larger scale: Gallic acid mono-
hydrate (1.881 g, 10 mmol) was dissolved in distilled water
4
3
leukemic cells HL-60. With this in mind, we extended our
study by exploring the reactivity of gallic acid with another non-
toxic cation (here calcium), in order to assess the impact of the
composition and structure on the bioactivity of such materials.
Herein, we report the synthesis under hydrothermal condi-
tions of two novel 3-D calcium gallate coordination polymers.
Both crystal structures were solved by single-crystal X-ray
diffraction (XRD) and the solids were further characterized by
infrared (IR) spectroscopy, thermogravimetric analysis (TGA),
(100 mL) at room temperature. Calcium nitrate (1.181 g, 5 mmol)
was then added to the solution followed by a KOH 5 M solution
which was added dropwise until the solution reached pH 9. The
reaction solution was heated under reflux for 24 h.
MIL-156: [Ca K (H O) (gal) ]ꢁnH O (n = 4–6). Gallic acid
3
2
2
2
2
2
2
N porosimetry and temperature dependent powder XRD. In
monohydrate (0.188 g, 1 mmol) was dissolved in distilled
water (10 mL) at room temperature. Calcium hydroxide (0.074 g,
addition, their chemical stability was evaluated, both in water
and in a more complex simulated physiological medium.
Finally, the potential protective antioxidant bioactivity of these
solids was assessed by means of the reactive oxygen species
1
mmol) was then added to the solution followed by a KOH 5 M
solution which was added dropwise until the solution reached pH
4 (B800 mL = B4 mmol). The reaction mixture was then sealed
in a Teflon lined autoclave reactor, placed in an oven, heated up to
20 1C in 1 h, and then kept at this temperature for 24 h; the final
1
(ROS) production, investigating their in vitro biocompatibility
by different cellular viability and cell proliferation/death balance
assays.
1
pH was B14. Once cooled to room temperature the resulting solid
was filtered, repeatedly washed with distilled water and dried at
room temperature to reveal needle like crystals.
Experimental section
Materials
Single crystal X-ray diffraction
Gallic acid monohydrate (C H O ꢁH O) (Sigma Aldrich,
MIL-155: [Ca (H O)(H gal) ]ꢁ2H O. The crystals were too
7
6
5
2
2
2
2
2
2
Z98.0%), calcium nitrate tetrahydrate [Ca(NO
3
)
2
]ꢁ4H
2
O (Carlo small to be studied using a conventional laboratory diffracto-
Erba Reagents, 99.0–103.0%), calcium hydroxide Ca(OH)
2
meter. The structure was then determined for a microcrystal
(
Aldrich 95%) and KOH pellets (Alfa Aesar, 85%) were obtained (dimensions: 0.02 ꢂ 0.02 ꢂ 0.004 mm; Table S1, ESI†) from the
commercially and used without any further purification. Phos- data collected on the CRISTAL beamline at Synchrotron Soleil,
phate buffered saline (PBS) solution (0.01 M, pH = 7.4), RPMI using a set up adapted for small crystals at 100(2) K on an
1
640 medium supplemented with GlutaMAXt, penicillin– Xcalibur Atlas four-circle diffractometer and equipped with
ꢀ1
streptomycin (5000 U mL ) and heat-inactivated fetal bovine a CCD plate detector. Data reduction was performed using
serum (FBS) were provided by Gibco -Life Technologies (see CrysAlis. An empirical absorption correction was applied using
s
ref. 44 for composition). Similarly, dimethylsulfoxide (DMSO; spherical harmonics on the basis of multiple scans of equi-
Z99.7%) and thiazolyl blue tetrazolium bromide (MTT) were valent reflections, implemented in the SCALE3 ABSPACK scaling
purchased from Sigma Aldrich (St Louis, MO), whereas the algorithm.
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MIL-156: [Ca (H O) (gal)
Paper
3
K
2
2
2
2
]ꢁnH
2
O (n = 4–6). For MIL-156, PBS solution (0.04 M, pH 2.5), injecting 10 mL as the sample
ꢀ
1
the crystals were of sufficient size to be measured using volume under a flow rate of 1 mL min and with 25 1C as the
a laboratory diffractometer. The chosen crystal (dimensions: column temperature. Different solutions of free gallic acid were
0
.2 ꢂ 0.04 ꢂ 0.03 mm; Table S1, ESI†) was analysed at room analysed as standards for the calibration curve in the range of
ꢀ1
temperature 293(2) K using a Bruker Nonius X8 APEX 1.00–0.01 mg mL (correlation coefficient 40.99). Note that
diffractometer equipped with a CCD area detector. SAINT the limit of quantification of gallic acid was estimated to be
ꢀ1
software was used to integrate and scale intensities and a 3.7 mg mL . A chromatogram of the standards showed a
semi-empirical absorption correction (SADABS) was applied retention time for gallic acid at 2.7 min with an absorption
4
5,46
on the basis of multiple scans of equivalent reflections.
maximum at 210 nm.
Finally, the degradation kinetics of
The structures of both MIL-155 and MIL-156 were solved by Mg(H
2
gal), MIL-155 and MIL-156 were represented as the wt%
direct methods using SHELXS-97 and refined with the full of the linker released.
matrix least squares routine SHELXL-97. Non H-atoms were
In vitro studies
refined anisotropically. The aromatic protons attached to gallate
ligands were added as rigid bodies whilst acidic hydrogen atoms
and the ones bound to the water molecules in MIL-155 were (ATCC HTB-177TM, ATCC TIB-71TM and ATCC CCL-240TM,
Cells and culture. NCI-H460, RAW-264.7 and HL-60 cell lines
s
s
s
located using difference Fourier maps, taking into account the respectively) were cultured in RPMI 1640 GlutaMAXt, supplemen-
ꢀ
1
results of the bond valence calculation (see the discussion ted with 10% FBS, and 100 units mL of penicillin/streptomycin.
below). The exact positions of the protons in the water molecules Cell lines were grown at 37 1C in a humidified 5% CO
2
in MIL-156 have not been determined.
Crystallographic and refinement parameters are summarised
in Table S1 (ESI†).
atmosphere.
Cytotoxicity assays. The cytotoxic activity of Mg(H gal),
MIL-155 and MIL-156 as well as their precursors (Mg(OH)2,
2
Ca(NO
Annexin assays.
3
)
2
, Ca(OH)
2
and H
4
gal) was analysed by the MTT and
Physicochemical characterisation
47,48
Adherent NCI-H460 and RAW-264.7 cells
TGA analysis was carried out using Mettler Toledo TGA/DSC 1, were seeded 24 h prior to the assay in 96-well plates at a density
s
ꢀ1
4
STAR System apparatus under O
2
, at a heating rate of 3 1C min
of 1 ꢂ 10 cells per well in RPMI supplemented with 10% FBS.
up to 800 1C. X ray powder diffraction (XRPD) patterns were The HL-60 cell line, with cells in the suspension, was used
5
collected at 293 K on a Siemens D5000 Diffractometer working in directly at a density of 1 ꢂ 10 cells per well in RPMI supple-
the (y–2y) mode by using CuKa radiation. X-ray thermodiffraction mented with 10% FBS. The treatments were prepared at a
was performed using a y–y Bruker D8 Advance diffractometer 10-fold higher concentration (due to a direct 1/10 direct dilution
equipped with a HTK-1200N (Anton Parr) high temperature in the well, as 30 mL of the sample in PBS were added to a final
chamber and a LYNXEYE XE detector (Cu radiation). Diagrams volume of 300 mL per well). Based on this first concentration, a
2
were collected every 10 1C between 20 and 300 1C. IR spectra were dilution series of Mg(H gal), MIL-155 and MIL-156 were per-
recorded using a Nicolet 6700 FT-IR Thermo Scientific spectro- formed with cell culture media, yielding different concentrations
ꢀ
1
ꢀ1
meter between 500 and 4000 cm (Fig. S2, ESI†).
(from 250 to 1 mg mL ). Subsequently, all these stimuli were
Prior to the N sorption measurements, samples were heated added to the cells for 24 h, keeping them at 37 1C under a 5%
2
overnight at 100 1C under primary vacuum (BEL Japan, BELSORP CO2 atmosphere in both experiments. From one site, the
Prep). Then, N sorption isotherms were collected at 77 K on a cytotoxicity was determined by adding the MTT reactant
2
ꢀ1
BEL Japan Belsorp Mini apparatus.
(0.5 mg mL in PBS, incubation at 37 1C for 2 h) after the
contact time, followed by a PBS washing with 200 mL, ending
with 100 mL of DMSO added to each well, together with their
Degradation tests
4
9
2
The release of gallic acid from Mg(H gal), MIL-155 and MIL-156 measurement of the absorbance (at l = 539 nm) after stirring.
was performed in triplicate (corresponding to the average The results are summarised in Fig. S4 (ESI†). In addition, the
obtained in two independent experiments [n = 6] and the error cytotoxicity was measured by determination of the apoptotic
bars corresponding to the standard deviation) by soaking 12 mg and necrotic index after 24 h in contact with the treatment. The
of each solid in 12 mL of aqueous solution (Milli-Q water) and cells were analysed using an Annexin-V FITC kit (Immunostep,
5
0,51
in a cell culture medium (RPMI) at 37 1C under continuous Salamanca, Spain), following manufacturer’s instructions.
stirring. After different incubation times (1, 4, 8 and 24 h), an Briefly, after the contact of the cells with the material, they were
aliquot of the supernatant was recovered by centrifugation stained with an Annexin probe, which binds to phosphatidylserine
(14 500 rpm, 15 min). The monitoring of the gallic acid release at the outer cell membrane, detecting cell apoptosis. Propidium
was carried out through a reversed phase high performance iodide (PI) was used to quantify necrotic cells, since this dye stains
liquid chromatography (HPLC) system from Waters (Waters DNA after the membrane becomes permeable to PI. Data acquisi-
Alliance E2695 separations module) with a Sunfire-C18 reverse- tion and analysis were done by flow cytometry (BD Accurit C6,
phase column (5 mm, 4.6 ꢂ 150 mm from Waters) and equipped Biosciences) using Accuri software. For each analysis, 10000 events
with a Waters 2998 variable-wavelength photodiode array detector, were acquired, detecting FITC and PI fluorescence in the green
controlled using Empower software. The mobile phase used for and red fluorescence channels, respectively. The results are
the measurements consisted of a mixture of 45% v/v methanol in summarised in Fig. S5 and S6 (ESI†).
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ROS production. The cells were seeded in 96-well plates
5
(
U bottom) at a density of 1 ꢂ 10 cells per well in 100 mL of cell
culture medium (RPMI supplemented with 10% FBS). The
stimulus-containing solutions of 100 mL were added to the cells
ꢀ
1
at final concentrations of 5, 15, 30 and 60 mg mL of either
MOFs such as Mg(H gal), MIL-155 and MIL-156 or their pre-
cursors (Mg(OH) , Ca(NO , Ca(OH) and H gal). Basal and
2
2
3
)
2
2
4
negative controls were considered as the cells in the absence
of stimulus and the cells in the presence of a ROS reactant
0 0
(
2 ,7 -dichlorofluorescein diacetate, DCFH-DA, Invitrogent),
respectively. As the positive control, the cells were incubated
with an oxidant component, phorbol 12-myristate-13-acetate
PMA (10 mM) at 37 1C. After 8 h of incubation, cells were
centrifuged (900 rpm, 5 min) and kept in contact with the
ROS reactant, (1 mL per 200 mL of cells) for 30 min at 37 1C
under dark conditions. Two PBS-washes were performed after
0
0
the incubation and, finally, the 2 ,7 -dichlorofluorescein (DCF)
fluorescence in cells was measured using flow cytometry (BD
TM
Accuri
C6 Flow Cytometer) on the total living population
All data are presented in Fig. 5 and Fig. S3 (ESI†).
5
2,53
region.
Results and discussion
Synthesis and crystal structures
4
The reactivity of H gal with calcium salts in water under
hydrothermal conditions was thoroughly investigated. By
systematically varying the pH of the reaction mixture (upon
addition of a KOH solution), it was possible to isolate two
crystalline phases, both in a pure form (see Fig. S1 (ESI†)
for XRD powder patterns). The first compound, denoted as
MIL-155 (MIL stands for Materials Institute Lavoisier), was
Fig. 1 Structure of MIL-155: (a) general view along the a axis; (b) double
isolated under slightly basic conditions with pH ranging from chain of corner and edge sharing CaO polyhedra; (c) coordination feature
7
7
–8 to 10 (the best crystallinity at pH = 8–9), whereas pH of both independent gallate ligands.
ranging from 11 to 13 leads to an amorphous product and/or
CaCO ; a second hybrid solid, namely MIL-156, could be
3
isolated under very basic conditions (pH = 14).
Ow2 and Ow3 (Fig. 1a). As shown in Fig. 1c, both ligands adopt
MIL-155: [Ca
2
(H
2
O)(H
2
gal)
2
]ꢁ2H
2
O. As detailed below, single different coordination environments: galA is connected to six
crystal X-ray diffraction analysis (see Table S1, ESI† for refine- Ca cations (3 ꢂ Ca1, 3 ꢂ Ca2), two being chelated by the phenolic
ment details) revealed that both solids are 3-D coordination oxygen and four being connected through the carboxylate ones,
polymers. Nevertheless, both the nature of the inorganic sub- whereas galB is coordinated to only three Ca ions (2 ꢂ Ca1, 1 ꢂ Ca2),
units and the protonation state of the ligands differ. Further- two being connected through phenolic oxygens (one chelated, one
more, potassium ions are present in the structure of MIL-156 singly bound), one through the carboxylate one. Structural analysis,
and absent from MIL-155.
in combination with IR spectroscopy, was further used to determine
MIL-155 crystallises in a triclinic setting, space group P1%, a plausible protonation state of the constituents. Bond valence
with two Ca (Ca1 and Ca2), two gallate (galA and galB) and three calculation (see Table S2, ESI†) indicates that Ow1 is indeed a
ꢀ
2ꢀ
water molecules (Ow1, Ow2, Ow3) in a general position, leading bridging water molecule rather than an anionic (OH , O ) ligand.
to the formula [Ca (H O)(H gal) O. Both calcium cations Considering the Ca to ligand ratio (1 : 1), it is thus expected that the
]ꢁ2H
are surrounded by 6 oxygen atoms from the ligands (both ligands are only partially deprotonated, with two acidic protons
2
2
2
2
2
2ꢀ
2
carboxylate and phenolate) and one water molecule (Ow1). remaining (H gal ). Indeed, an adsorption band in the infrared
ꢀ
1
The CaO7 polyhedra connect to each other through both spectrum at 3400 cm , attributed to acidic O–H groups, confirms
corners and edges to define double chains running parallel to this hypothesis (Fig. S2, ESI†). For ligand H galA, bond valence
2
the a axis (Fig. 1b). These inorganic chains are further inter- calculations (Table S2, ESI†) suggest that both meta-phenoxy oxygen
connected through both galA and galB ligands, both parallel to atoms (O3 and O5) are protonated, while other oxygen atoms
the b, c plane to define small rectangular channels running (O1, O2, O4) are deprotonated, similar to what was found in the
II
41–43
along the a axis and containing free water molecules, namely already reported solids M (H
2 2
gal)ꢁ2H O.
The comparison of
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the C–O bond lengths in both solids (Table S3, ESI†) also seems
to support this finding. For ligand H galB, bond valence calcula-
2
tions only allowed us to establish the protonation state for the
coordinated phenolic oxygen (O14 and O15): the meta-oxygen
(O15) appears protonated, while the para one (O14) is deproto-
nated (Table S2, ESI†). For the uncoordinated meta-oxygen (O13),
the examination of the C–O bond length (Table S3, ESI†) also
suggests that it is protonated. Taking this assumption into
account, the uncoordinated carboxylate oxygen must be depro-
tonated in order to reach an overall charge of ꢀ2. Partial
disorder of the acidic proton cannot of course be ruled out.
However, the examination of the IR spectrum, for which no band
characteristic of the CQO vibration of a carboxylic acid group
ꢀ
1
was detected (region 1700–1660 cm , see Fig. S2, ESI†), further
validates this model. Plausible positions of the hydrogen atoms
bonded to meta-phenolic oxygens and of the water molecules
were thus finally deduced from the Fourier map. The presence of
both acidic protons of the ligand and bound and free water
molecules leads to a complex hydrogen bond network involving
all these constituents (see Table S4, ESI† for related distances
and angles).
Although the protonation state of the gallate ligands and the
formula of MIL-155 are similar to the known M(II) gallate
4
1–43
solids,
both compounds are not isostructural. The difference
mainly relies on the coordination state of the Ca ions: its larger
ionic radius allowed a coordination number higher than six
(here seven), hence leading to a completely different structure.
MIL-156: [Ca K (H O) (gal) ]ꢁnH O (n B 4–6). MIL-156
3
2
2
2
2
2
crystallises in an orthorhombic setting, space group Pccn,
with one Ca ion lying on a two-fold axis, and one Ca cation,
one K cation, one gallate ligand and four water molecules,
among which one presents a 0.5 occupancy, in the general
Fig. 2 Structure of MIL-156: (a) general view along the c axis; (b) ribbon of
edge sharing CaO
gallate ligand.
6 8
and CaO polyhedra; (c) coordination feature of the
position, giving rise to the formula [Ca
3
K
2
(H
2
O)
2
(gal)
2
]ꢁnH
2
O,
n B 5. One of the Ca ions (Ca1) is octahedrally coordinated by
four ligand-related oxygen atoms and two water molecules
(
Ow1), whereas the second one (Ca2) is 8-fold coordinated (see Table S5, ESI† for distances) and free water molecules.
solely by phenolic oxygens. Both polyhedra share edges to If one considers the structure along the c axis, one can point out
define inorganic ribbons running along the c axis (Fig. 2b). that the potassium cation sits very close to the centre of the
The gallate moieties connect these ribbons along the a + b and aromatic ring of the gallate ligand (3.15 o dCꢁ ꢁ ꢁK o 3.41 Å),
a ꢀ b directions to define a 3-D framework with channels hence suggesting the occurrence of an electrostatic supra-
+
55
running parallel to the ribbons and filled with both potassium molecular K –p interaction (Fig. S3, ESI†). Finally, free and
ions and free water molecules (Fig. 2a). Each ligand interacts with bound water molecules together with the pendant oxygen atom
six Ca ions (see Fig. 2c), with only one singlet oxygen (from the from the carboxylate group are involved in a 1-D hydrogen bond
carboxylate group) not involved in the coordination bond. Again, network deploying along the channel axis (see Table S6, ESI†
bond valence calculation confirmed that Ow1 is a bridging water for characteristic distances).
molecule and not an anionic ligand (Table S5, ESI†). Taking
into account the formula, the gallate ligand must be totally
Physicochemical characterisation
deprotonated. This is again in reasonable agreement with bond In order to investigate the thermal behaviour of MIL-155 and
valence calculation (Table S5, ESI†) and with the IR analysis, for MIL-156, both TGA and temperature dependent powder XRD
which, in contrast to MIL-155, no acidic proton is detected in the experiments were carried out under oxygen and air atmospheres,
ꢀ
1
3
400–3500 cm region (Fig. S2, ESI†). This can, of course, be respectively (see Fig. 3).
explained by the more basic synthetic conditions, implying a The TGA curve of MIL-155 (Fig. 3a) shows two weight losses
more negatively charged ligand, resulting in a higher M/L ratio, below 200 1C (in the 60–100 and 140–190 1C ranges), associated
54
and hence a higher degree of inorganic condensation.
with the departure of both free and bound water molecules
Potassium ions are lying in the channels to balance the (weight losses: obs. 10.5%, cal. 11.5%). Such departure leads to slight
charge, interacting weakly with meta-phenolic oxygen atoms structural changes, as detected on the thermodiffractogram (Fig. 3b).
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Above 230–250 1C, the combustion of the ligand gives rise to the (HL-60), human non-small lung cancer (NCI-H460) and murine
collapse of the framework and the successive formation of leukemic monocyte (RAW-264.7)) by means of the cell viability
CaCO (470 o T o 560 1C, weight losses: obs. 53%, cal. 57%) MTT assay (see the Experimental section). Remarkably, very low
3
and CaO (T 4 670 1C, weight losses: obs. 74%, theo. 76%) is cytotoxicity profiles were observed after 24 h of cell contact time
likely. For MIL-156, two weight losses, likely associated with the (Fig. S4, ESI†), associated with important values of the half
ꢀ1
departure of most of the water molecules (weight losses: obs. maximal inhibitory concentration (IC50 = 125 and 250 mg mL
6%, cal. 14 and 19% for the departure of only free and both for MIL-155 and MIL-156, respectively, regardless of the cell
1
bound and free water molecules respectively) are also found line). The lower toxicity of MIL-156 could be related to its
below 150 1C (Fig. 3a). The second one is associated with a higher chemical stability (see below). Note here that totally
major structural modification (see Fig. 3c); the resulting com- comparable IC50 values were also obtained for the already
4
3
pound, although less crystalline than the pristine one, remains reported Mg(H gal).
2
ordered up to 300 1C. Above 150 1C, the TG curve (Fig. 3a)
Then, in order to provide some information about the cell
presents a slightly decreasing plateau up to 530 1C, followed by proliferation/cell death balance as well as the potential activa-
5
0,51
two major losses, likely leading to CaO and K
losses: obs. 51%, cal. 53%).
2
CO
3
(weight tion of a specific death pathway, Annexin-V-FITC assays
were carried out using the HL-60 cell line (see the Experimental
As both MIL-155 and MIL-156 were found to present section). In these studies, the living cells, early and late
channels filled with water molecules, their porosity was evaluated apoptosis cells (programmed cell death by normal and healthy
by means of nitrogen adsorption measurements at 77 K. After process) together with necrotic cells (cell death that is triggered
activation under primary vacuum overnight at 100 1C, neither of by external factors, such as trauma or infection) can be dis-
ꢀ1
them was found to adsorb a significant amount of nitrogen.
tinguished. At low concentrations (r30 mg mL ), both Ca
gallates showed the high presence of living cells (Z75% after
24 h, Fig. S5, ESI†). One can nevertheless point out a slight
Bioactivity
increase of the early apoptotic cells percentage in contact with
Biocompatibility evaluation. The in vitro toxicity of different
concentrations of MIL-155 and MIL-156 was firstly evaluated
in three different cell lines (human promyelocytic leukaemia
ꢀ
1
intermediate concentrations (30–60 mg mL ), reaching a sub-
stantial late apoptotic state (B88%) for MIL-155 at higher
ꢀ1
concentrations (Z60 mg mL ). On the other hand, MIL-156
4
3
exhibited similar patterns to Mg(H gal), with B50% of late
2
ꢀ
1
apoptotic cells, observed at higher concentrations (125 mg mL ).
These results are in accordance with the higher cell viability of
MIL-156 when compared with MIL-155 (see above). Additional
experiments, performed on the isolated constituents (Ca(NO
Ca(OH) and H gal; Fig. S6, ESI†), indicate that the cell toxicity
observed at high concentrations arises from the ligand
20 vs. o 2% of apoptotic cells in H gal vs. the cation pre-
cursors, respectively). This is in agreement with previous data
3 2
) ,
2
4
(
4
4
3
reported for the Mg(H gal), in which the high concentration
2
of phenolic components was associated with a pro-oxidant
behaviour, inducing the apoptotic cell death by oxidative
5
6
degradation.
On the whole, these solids seem to exhibit good in vitro
biocompatibility.
Antioxidant activity and stability studies. Considering the
probed antioxidant effect of the constitutive gallate ligand and
4
3
our first results on the Mg(H gal) solid, the potential anti-
2
oxidant activity of MIL-155 and MIL-156 was assessed by
evaluating the production of Reactive Oxygen Species (ROS)
from cells in contact with an increasing amount of MOF (from
ꢀ
1
5
to 60 mg mL ). The macrophage lineage HL-60 was selected
here since it has been widely recommended as a model for the
5
3
study of the cellular oxidation state. Two controls were first
considered: a positive control C+, incubating the cells with an
oxidant molecule (ROS inducer), namely phorbol 12-myristate-
1
3-acetate (PMA), and a negative control Cꢀ, incubating the
cells without treatment. After 8 h contact time, the incubation
with dichlorofluorescein diacetate (DCFH-DA, ROS reactant)
allowed the revealing of the diverse oxidation states of the cells
Fig. 3 Thermal behaviour of MIL-155 and MIL-156: (a) thermogravimetric
2
analyses (under O ); (b and c) temperature dependent powder XRD
analysis of MIL-155 and MIL-156 respectively (under air).
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by flow cytometry. A third control, namely the basal control (neither the ROS inducer nor the ROS reactant) was also
basal, in which the cells were subjected to no treatment at all considered (see the Experimental section). The results are
C
Fig. 4 ROS production of HL-60 cells in contact with Mg(H
and positive (cells + DCFH-DA + PMA) controls are disclosed as black, grey and red lines, respectively. Several concentrations (5, 15, 30 and 60 mg mL
2
gal) (top), MIL-155 (middle) and MIL-156 (bottom). Basal (cells), negative (cells + DCFH-DA)
ꢀ1
)
were tested, and are pictured in orange, green, blue and pink, respectively. Note that these data, corresponding to one of the triplicates obtained in four
independent experiments (n = 12), are totally representative from the whole results. Left and right sides correspond to the cells with or without a ROS
inducer (PMA), respectively.
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summarised in Fig. 4, left. Interestingly, while almost no
change of the ROS production compared to the negative control
was detected for MIL-156 whatever the concentration, a second
peak shifted towards the basal control occurs for MIL-155,
being consistent with a concentration-dependent antioxidant
activity (Fig. 4, left). With the aim of elucidating the role of both
gallate and calcium constituents, the ROS activity was deter-
mined for the synthesis precursors (Fig. S7, ESI†). If none of the
calcium precursors (Ca(OH)
2 3 2
and Ca(NO ) ) lead to a significant
effect on the oxidation state of the cells, the gallic acid showed,
4
3
as expected, a noticeable antioxidant effect. As MIL-155
and MIL-156 are built up from the same constituents, further
studies were carried out to understand their drastically different
antioxidant activity. The chemical stabilities of both solids were
evaluated by suspending the solids in different media at 37 1C:
(i) a simple aqueous solution was used to mimic the degradation
of the solids under cutaneous administration, considering their
potential cosmetic interest; and (ii) cell culture medium (RPMI),
in order to correlate the observed antioxidant activity with the
release rate of the constitutive components of the solids into the
cellular environment, where the antioxidant assays took place.
After 24 h of incubation, the chemical degradation was evaluated
by means of the gallate ligand release into the media, deter-
mined by HPLC (see the Experimental section).
Remarkably, as shown in Fig. 5, while MIL-156 exhibits a
high chemical stability regardless of the media, with almost no
release of its constitutive gallate ligand to the media (0.05 ꢃ
0
.01 vs. 0.4 ꢃ 0.1% in water and RPMI, respectively), MIL-155
progressively degrades within water and RPMI (after 24 h, 27 ꢃ
2% and 48 ꢃ 22, respectively). Such a difference in solubility
can be related to their different crystal structures: MIL-156 is
1
4ꢀ
built up from a fully deprotonated ligand (gal ), whereas MIL-155 Fig. 5 Degradation profile of Mg(H
possesses a less negatively charged ligand (H gal ), resulting in
2
2
gal), MIL-155 and MIL-156 in aqueous
2ꢀ
and cell culture media (RPMI) at 37 1C.
stronger ligand-cation bonds for MIL-156. This is confirmed by the
comparison of MIL-155 and Mg(H gal): despite the different nature
2
and coordination sphere of the cation, the same protonation state would depend not only on the material concentration but also
for the ligand leads to very similar dissolution profiles, regardless on its degradation rate (time-dependent effect).
of the media (Fig. 5). Eventually, the absence of dissolution of
In parallel, the potential oxidative protective effect of the
MIL-156 explains the lack of antioxidant activity of this solid, calcium gallates was also evaluated in the presence of oxidant
confirming that the effect is associated with the release of the species by keeping in contact the cells with different doses of
gallate ligand into the media.
MOF in the presence of PMA, a ROS inducer (Fig. 4, right). As
In this line, the present concentration-dependent antioxi- expected, MIL-156 exhibits a similar ROS production than the
dant activity supports the fact that the antioxidant effect is due positive control, in agreement with the absence of antioxidant
to the progressive delivery of its constituents. More precisely, activity due to its high chemical stability. Interestingly, MIL-155
depending on the dose of MIL-155, we can remarkably observe demonstrates a significant antioxidant protective effect, depen-
the emergence of a double cell population related to a different dent on the concentration. If one compares these results with
ꢀ
1
43
oxidation state, being more prominent from 30 mg mL (Fig. 4, the previously reported Mg(H
right). While the oxidation state of a fraction of the cells is not antioxidant activity, one can notice a higher efficacy for MIL-155.
affected by the presence of MIL-155, the ROS of the other cell Indeed, while only the highest tested doses of Mg(H gal)
population is notably shifted to the negative control values, (60 mg mL ) show antioxidant activity, MIL-155 shows a protec-
2
gal), also exhibiting a protective
2
ꢀ
1
ꢀ
1
even reaching a similar oxidation state than the basal control. tive activity at much lower concentrations (from 5 mg mL
;
The proportion of this last population strongly depends on the Fig. 4, right). If one considers the concentration of released
dose of the solid in contact with the HL-60 cells. These gallate in solution, very similar amounts are detected within the
ꢀ
1
observations suggest that the amount of gallate released from medium for both solids (0.17 vs. 0.19 mg mL for MIL-155 and
the material degradation is not able to affect the total pull Mg(H gal), respectively). This suggests an influence of the cation
of cells, but only a fraction. Therefore, the antioxidant effect on the oxidant effect. In contrast to magnesium, calcium is
2
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known to be indirectly involved in the ROS balance. Indeed, high Programme (Marie Curie Actions) of the European Union’s Seventh
intracellular calcium levels can induce ROS production, which is Framework Programme (FP7/2007-2013) under REA grant agree-
associated with the disruption of the mitochondrial membrane, ment no. 291803. The authors thank the synchrotron Soleil for
5
7,58
and consequently, with cell apoptosis.
However, this seems providing access to the beamline CRISTAL.
to be in contradiction with our findings, evidencing a lower
ROS. Although more specific studies are needed to elucidate
the antioxidant mechanism, one could hypothesise that the
presence of the gallate linker can also modify the intracellular
calcium levels (by coordination, for instance).
Notes and references
1 Special issue, Chem. Soc. Rev., 2009, 38(5).
2
3
4
Special issue, Chem. Rev., 2012, 112(2).
Special issue, Chem. Soc. Rev., 2014, 43(16).
J. Della Rocca, D. Liu and W. Lin, Acc. Chem. Res., 2011,
Conclusions
4
4, 957.
Two new 3-D coordination polymers, namely MIL-155 and
MIL-156, built up from both Ca and gallic acid were prepared,
and their crystal structures were determined; both solids
exhibit a suitable biocompatibility, as evidenced by the high
cell viability and the low presence of apoptotic cells when
several cell lines were incubated with the solids. While made
of the same constituents, these solids exhibit different compo-
sition and crystal structures, leading to very distinct solubility
profiles in relevant simulated biological media and hence
different biological activities. Whereas MIL-156 does not present
any antioxidant effect because of its high chemical stability, the
progressive release of the gallate ligand from the less stable
MIL-155 leads to a remarkable protective antioxidant effect, which
5
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