A Biocompatible Aspartic-Decorated Metal–Organic Framework with Tubular Motif Degradable under Physiological Conditions

Abstract

Achieving a precise control of the final structure of metal–organic frameworks (MOFs) is necessary to obtain desired physical properties. Here, we describe how the use of a metalloligand design strategy and a judicious choice of ligands inspired from nature is a versatile approach to succeed in this challenging task. We report a new porous chiral MOF, with the formula Ca5II{CuII10[(S,S)-aspartamox]5}·160H2O (1), constructed from Cu²⁺ and Ca²⁺ ions and aspartic acid-decorated ligands, where biometal Cu²⁺ ions are bridged by the carboxylate groups of aspartic acid moieties. The structure of MOF 1 reveals an infinite network of basket-like cages, built by 10 crystallographically distinct Cu(II) metal ions and five aspartamox ligands acting as bricks of a tubular motif, composed of seven basket-like cages each. The pillared hepta-packed cages generate pseudo-rhombohedral nanosized channels of ca. 0.7 and 0.4 nm along the b and a crystallographic axes. This intricate porous 3D network is anionic and chiral, each cage displaying receptor properties toward three-nuclear [Ca3(μ-H2O)4(H2O)17]⁶⁺ entities. 1 represents the first example of an extended porous structure based on essential biometals Cu²⁺ and Ca²⁺ ions together with aspartic acid as amino acid. 1 shows good biocompatibility, making it a good candidate to be used as a drug carrier, and hydrolyzes in acid water. The hypothesis has been further supported by an adsorption experiment here reported, as a proof-of-principle study, using dopamine hydrochloride as a model drug to follow the encapsulation process. Results validate the potential ability of 1 to act as a drug carrier. Thus, these make this MOF one of the few examples of biocompatible and degradable porous solid carriers for eventual release of drugs in the stomach stimulated by gastric low pH.

Full text

A Biocompatible Aspartic-Decorated Metal−Organic Framework
with Tubular Motif Degradable under Physiological Conditions
Marta Mon, Rosaria Bruno, Rosamaria Lappano, Marcello Maggiolini, Leonardo Di Donna,
Jesus Ferrando Soria,*Donatella Armentano,*and Emilio Pardo*
Cite This: https://doi.org/10.1021/acs.inorgchem.1c01701
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ABSTRACT: Achieving a precise control of the final structure of
metal−organic frameworks (MOFs) is necessary to obtain desired
physical properties. Here, we describe how the use of a
metalloligand design strategy and a judicious choice of ligands
inspired from nature is a versatile approach to succeed in this
challenging task. We report a new porous chiral MOF, with the
formula Ca5II{CuII10[(S,S)-aspartamox]5}·160H2O(1), con-
structed from Cu2+ and Ca2+ ions and aspartic acid-decorated
ligands, where biometal Cu2+ ions are bridged by the carboxylate
groups of aspartic acid moieties. The structure of MOF 1reveals
an infinite network of basket-like cages, built by 10 crystallo-
graphically distinct Cu(II) metal ions and five aspartamox ligands
acting as bricks of a tubular motif, composed of seven basket-like
cages each. The pillared hepta-packed cages generate pseudo-rhombohedral nanosized channels of ca. 0.7 and 0.4 nm along the b
and acrystallographic axes. This intricate porous 3D network is anionic and chiral, each cage displaying receptor properties toward
three-nuclear [Ca3(μ-H2O)4(H2O)17]6+ entities. 1represents the first example of an extended porous structure based on essential
biometals Cu2+ and Ca2+ ions together with aspartic acid as amino acid. 1shows good biocompatibility, making it a good candidate
to be used as a drug carrier, and hydrolyzes in acid water. The hypothesis has been further supported by an adsorption experiment
here reported, as a proof-of-principle study, using dopamine hydrochloride as a model drug to follow the encapsulation process.
Results validate the potential ability of 1to act as a drug carrier. Thus, these make this MOF one of the few examples of
biocompatible and degradable porous solid carriers for eventual release of drugs in the stomach stimulated by gastric low pH.
■INTRODUCTION
Metal−organic frameworks (MOFs)
1−3
have become a hot
topic of research during the past decades due to the
concomitant presence of atheistically pleasant porous high-
dimensional structures with intriguing net topologies and
thrilling chemical and physical properties. Indeed, these hybrid
materialsconsisting of metal ions (or small metal clusters)
linked by a wide diversity of organic spacershave been able
to make themselves a functional entity by controlling the
assembling of their subunits, which have enabled them to find
applications in gas storage and separation,
4−6
drug delivery,
7−9
molecular recognition,
10−,14
and catalysis
15−18
as well as in
templating the in situ growth/encapsulation of a wide variety of
functional moieties
19,20
Biomedical applications of MOFs are still in their infancy,
but encouraging results have been developed in the past years.
A quite recent step is the bioengineering of MOFs for the
design of original examples of MOFs using biomolecules that
constitute the bricks of life. This subclass of materials, referred
to as bioMOFs,
21,22
can be obtained using ligands derived from
simple amino acids,
23
nucleobases
24
and aminosaccharides,
25
or their larger derivatives polypeptides,
26
polynucleotides, and
polysaccharides, and even small proteins,
27
nucleic acids, or
complex sugars (like glycogen). BioMOFs may offer remark-
able advantages over traditional MOFs: (i) the possibility to
achieve homochiral solids crystallizing in polar space groups in
a rational and predictable way with applications in chiral
discrimination or separation, due to the enantiopure nature of
many biomolecules, (ii) large biocompatibility and feasibility in
medical applications, (iii) increased stability in hydrated
environments, and (iv) molecular recognition capabilities
reminiscent of biological processes. However, despite their
remarkable features, the strategy based on the direct synthesis
of bioMOFs with open-framework structures capable to host
and then align in their confined spaces the guest molecules/
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ions required to develop new biomimetic scaffolds has been
barely explored, and only a limited number of MOFs of
established biocompatibility have been reported
28−30
Thus,
more work is required to further increase our understanding on
such bio-mimicking host-guest interactions, and consequently,
open in the near future a myriad of potential biotechnological
applications.
In this context, aiming to make a step forward on current
limitations of bioMOFs and prompted by their properties, our
research efforts have been devoted to develop a programmed
strategy for the rational design of these materials focused on a
family of enantiopure disubstituted oxamidato ligands derived
from natural amino acids.
31,32
In particular, we have been able
to obtain different examples of three-dimensional bioMOFs,
where their functionality has been directed by the chemical
nature of the residue of the constituent amino acid. Extending
the application of this concept, here we report the synthesis of
a novel chiral oxamidato-based bioMOF, of formula
Ca5II{CuII10[(S,S)-aspartamox]5}·160H2O(1), (H2Me2-(S,S)-
aspartamox = bis[(S)-dimethylaspartate]oxalyl diamide,
Scheme 1) prepared from a ligand derived from the natural
amino acid L-aspartic acid, which displays receptor properties
toward three-nuclear calcium(II) entitieswhere Ca2+ ions are
highly solvated, mimicking the environment of biological
systems.
33−35
1represents a potential playground to gain
insight and, later on, try to mimick the possible binding sites of
the complex supramolecular assemblies acting in many
biological Ca2+ dependent processes, such as in the Ca2+
binding proteins, Calmodulin (CaM). In addition, the
biocompatibility of 1has been demonstrated with MTT assays
on MCF7 and SkBr3 breast cancer cells, which together with
their degradability under physiological conditions and
confirmed capability to load small drug’s molecules, open the
way for the future application of 1for drug delivery.
■SYNTHESIS AND X-RAY CRYSTAL STRUCTURE
We report herein the application of the metalloligand design
strategy to obtain a novel biocompatible and water-stable 3D
MOF of formula Ca5II{CuII10[(S,S)-aspartamox]5}·160H2O
(1), which was obtained as blue irregular prisms by slow
diffusion of aqueous solutions containing stoichiometric
amounts of (Bu4N)2{Cu2[(S,S)-aspartamox](OH)2}·4H2O
and CaCl2in H-shaped tubes at room temperature.
The crystal structure of 1determined by single-crystal X-ray
diffraction unveiled that it crystallizes in the chiral P212121
space group of the orthorhombic system, with an absolute
structure parameter (Flack calculated with Parsons method)
36
of 0.046(5). The structure of 1reveals an infinite network of
basket-like cages presenting a narrow window with a van der
Waals diameter of ca. 8 Å and a cage size of ca. 268 Å3(Figures
1−3). The asymmetric unit is built by 10 crystallographically
distinct Cu(II) metal ions and five aspartamox ligands (Figures
2c, 3, and S1), together with five distinct Ca2+ metal ions and a
huge amount of water molecules (Figure S1). Each Cu10 cage
is further interconnected through hydroxyl functions of the
aspartic acid residues (Figure 2a,c) yielding left-handed helices,
as bricks of a tubular motif, composed of seven basket-like
cages each (Figure 2a,b) developing along the [010] direction.
Scheme 1. Chemical Structure of the Chiral
Bis(dimethylaspartate)oxalamide Ligand H2Me2-(S,S)-
aspartamox (a) and the Corresponding Dicopper(II) Motif
Building the MOF (b)
Figure 1. A portion of the crystal structure of 1viewed along the [010] direction: (a) The intricate porous 3D network generated by the
interconnection of “helices of cages”via four aspartic acid residues from adjacent ones. Each cage encapsulates [Ca3(μ-H2O)4(H2O)17]6+. In (b),
calcium clusters have not been depicted to show the overall Cu(II) 3D network. Copper and calcium atoms are represented by blue and gold
spheres, respectively, whereas the ligands are depicted as sticks.
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B

The intricate anionic, chiral, and porous 3D network is
generated by the interconnection of those helices with four
aspartic acid residues by means of bridging carboxyl and
hydroxyl groups from adjacent ones (Figure 1). Thus, the
pillared hepta-packed cages generate two nanosized channels
growing along the a(Figure S2) and bcrystallographic axes
(Figure 1 and Figure S3). The latter unveil an irregular shape,
pseudo-rhombohedral, exhibiting a virtual diameter of ca. 0.7
nm. The other one has a more squared shape with ca. 0.4 nm
as virtual diameter. As shown in Figures S2 and S3, both
channels are decorated by coordinated water molecules and
oxygen atoms from the ligand’s moieties, giving them a
hydrophilic character. It might also explain the large number of
water molecules embedded within the structure, together with
its capability to exchange them loading dopamine hydro-
chloride drug, likely stabilized by hydrogen bonds supra-
molecular interactions.
In 1, each cage hosts three-nuclear [Ca3(μ-H2O)4-
(H2O)17]6+ entities [Ca−O distances in the range of
2.320(3)−2.874(4) Å] (Figure 3c,d), where Ca2+ ions are
solvated, being surrounded by eight [Ca(1) and Ca(3)] or
nine [Ca(2)] water molecules. Further Ca2+ metal ions reside
in the interstitial voids and interact with the carboxyl fragment
of aspartic acid residues, contributing to interconnect the
basket-like Cu10 cages (Figures 1b and 3c,d). The position of
the calcium clusters in the cages of 1unveils that it occurs
through a molecular recognition process, governed by H-bonds
involving water molecules surrounding alkaline-earth metal
ions and carboxyl and hydroxyl groups of the aspartic acid
moieties (Figure 3d). The 10 crystallographically distinct Cu2+
metal ions adopt highly distorted octahedral (CuN2O3Owater or
CuNO4OWor CuN3O2Ow) coordination geometries (Figures
2a and S1). The aspartamox ligand exhibits a symmetric
coordination mode, involving COO−groups in metal binding.
It coordinates Cu2+ and Ca2+ metal cations, producing up to
five different environments for copper(II) ions (Figures 1 and
S4).
The cis oxamidato-bridged dicopper(II) units, {CuII2[(S,S)-
aspartamox]}, coordinate each other through bridging carboxyl
and hydroxyl groups in a zipper-like fashion (Figure 2c,d).
Taking a more in-depth look, each as-made dimer, featuring
two side-chains of aspartic acid, encompasses one carboxyl for
intradimer linking together with the hydroxyl one acting as a
linker to adjacent {CuII2[(S,S)-aspartamox]} moieties (Figures
2d,e and S4a)inaninterlocking fashion (Figure 2d). The
additional coordination of those residues with carboxyl “free”
groups toward Cu(II) (Figure S4b) or Ca(II) ions (Figure
S4c) ensures the cohesion of adjacent interlocked {CuII4[(S,S)-
aspartamox]2} units (Figure 2b,c), self-assembling 10 copper
ions unfolding the chiral basket-like cage. Noteworthy, not all
those free carboxyl terminations coordinate metal ions; a
portion of them decorate the two gateways of the cages being
stabilized by solvent molecules H-bonded to the cages. The
two gateways of the cages can be described as ribbons of copper
metal ions surrounded by aspartic acid residues pointing
toward metal ions or water molecules, while the barriers of the
cage are delineated by a robust oxamate core of the aspartamox
ligand (Figure 3c). Each Cu10L5as-made cage is four-linked by
four O atoms from aspartic residues acting as cluster’s
connectors of adjacent baskets (Figure 2a). Six-coordinated Cu
metal centers have similar Cu−O and Cu−N bond lengths,
either for the basal/equatorial planes [1.947(6)−2.049(6) and
1.916(8)−1.971(7) Å] or for apical ones [Cu−O: 2.337(6)−
2.980(7) Å], typical of axial elongated distortions as expected.
The basket-like cages show exceptional receptor properties
through multiple H-bonding interactions toward [Ca3(μ-
Figure 2. (a) Perspective view of hepta-packed cages generating helices, interconnected through carboxylic functions of the aspartic acid residues
with four other aspartic acid moieties by means of bridging carboxyl and hydroxyl groups from adjacent ones; (b) view of one helix along the b
crystallographic axis; (c) perspective view of basket-like cages built by 10 crystallographically distinct Cu(II) metal ions and 5 aspartamox; (d, e)
details on ligand coordination mode within each cage. Copper atoms are represented by blue spheres, whereas the ligands are depicted as blue and
red sticks for nitrogen and oxygen bonds, respectively.
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C

H2O)4(H2O)17]6+ hydrated clusters, which occupy the centers
of the holes (Figure 3). They are linked to the wall of the toric-
like anionic cage by means of strong hydrogen bonds
stabilizing the huge hydrated calcium environment reminiscent
of binding in Calmodulin. In this ubiquitously expressed Ca2+-
binding protein, the coordination to Asp amino acid is typically
mediated by water molecules that are hydrogen-bonded to the
side chain of the amino acid or through the backbone of amino
acids in general. In 1, it occurs thanks to oxygen atoms from
the terminal side of the aspartic acid residues and oxamate
ligand’s core, which act as hooks to anchor guest moieties to
the cage’s wall [OW···O distances varying in the range 2.74−
2.98 Å].
The structural analysis unveiled the occurrence of a large
number of crystallization water molecules (not modeled)
placed inside the hydrophilic channels developing along the a
and baxes. The resulting porous structure facilitates the
adsorption/desorption of the solvent from the crystal, as
shown by thermogravimetric analysis, but this process occurs
with the loss of the crystallinity. Without found solvent
molecules, the effective free volumes of 1are calculated by
PLATON analysis to be 55% of the crystal volume (9548.6 Å3
of the 17355.0 Å3of the unit cell volume). In accordance with
SCXRD analysis, the channels of 1are entirely filled by solvent
guests (1) interacting and stabilizing [Ca3(μ-H2O)4(H2O)17]6+
hydrated clusters (Figure 3d and crystallographic details in the
Supporting Information).
The crystal structure of 1was deconstructed by applying the
concept of the simplified underlying net and also using
TOPOSPRO software in order to get a brief topological
analysis. So, the basket-like cages (Figures S5−S7) can be
represented as a node connected to adjacent nodes at a
distance of ca. 15 Å. Thus, the overall structure unfolds a dia
net (Figures 4 and S5−S7).
Figure 3. Details on Cu10 cages: (a, b) side and top views of cages featuring a narrow window with a van der Waals diameter of ca. 8 Å and an
effective cage size of 268 Å3(highlighted by gold spheres); (c, d) side and top views of Cu10 cages embedding [Ca3(μ-H2O)4(H2O)17]6+ perfectly
recognized by means of H-bonds. Copper and calcium atoms are represented by blue and gold spheres or polyhedra, respectively, whereas the
ligands are depicted as blue and red sticks for nitrogen and oxygen bonds, respectively. O···OWhydrogen bonds have been depicted with red dashed
lines, respectively.
Figure 4. Schematic view of the dia net topology in 1.
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D

■THERMOGRAVIMETRIC ANALYSIS AND X-RAY
POWDER DIFFRACTION
The water content of 1was determined by thermogravimetric
analysis (TGA) under a dry N2atmosphere. It shows a fast
mass loss from room temperature to ca. 420 K, followed by a
plateau in the mass loss until decomposition starts. The
estimated percentage weight loss value of 43% (Figure S8 in
the Supporting Information) corresponds to 130 H2O
molecules. This slightly mismatch between estimated solvent
molecules by TGA and SQUEEZE total count of electrons
(vide infra) is most likely due to the fast loss of solvent, often
shown by such porous materials. The experimental powder X-
ray diffraction (PXRD) patterns of a polycrystalline sample of
1confirm the purity and homogeneity of the bulk sample
(Figure S9a,b) and that the 3D anionic network does not
experience significant phase transitions in the range of 100−
298 K.
■BIOCOMPATIBILITY AND DEGRADABILITY
PROPERTIES
MTT Assay. The effects of 1on cell viability were
determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide] assay. It is based on the
conversion of MTT to MTT formazan by mitochondrial
enzyme. Cells were seeded in quadruplicate using 96-well
plates in regular growth medium and grown until 70%
confluence. After that, cells were washed once they had
attached and then treated with 5 μM solution of 1in regular
growth medium. Relative cell viability was determined after 24,
48, and 72 h by MTT assay according to the manufacturer’s
protocol (Sigma-Aldrich, Milan, Italy). The cell viability was
expressed as a percentage of cells exposed to chemicals with
respect to vehicle treated cells. Remarkably, 1for 72 h did not
alter cell viability (Figure 5). These findings, even if
preliminary, suggest the good biocompatibility of 1making it
as a good candidate as a drug nanocarrier.
Loading Experiment. In order to test the ability of the
MOF to act as a drug carrier, an adsorption experiment has
been set up, as a proof-of-principle study of guest inclusion,
using dopamine hydrochloride as model drug for the
encapsulation process. 8.25 mg of MOF was soaked in 0.55
mL of a solution of dopamine hydrochloride at 4510 mg/L.
The concentration of the solution was monitored by high
performance liquid chromatography ultraviolet (HPLC/UV)
by picking up 30 μLatdifferent times (Figures 6 and S10).
Figure 6a shows the decreasing of concentration of dopamine
in the contact solution over a time period of 5 days. The
kinetics of the adsorption is shown in Figure 6b, which
describes the amount of dopamine adsorbed by the MOF
powder. It is worth to note that the amount of dopamine
adsorbed by the MOF after 5 days is around 62% of the initial
loading, providing an adsorption capacity of the material of
0.186 g of drug per gram of solid at the concentration studied.
Degradability Properties and pH Dependence Stud-
ies. To investigate the degradability of 1under gastric
physiological conditions, the dissolution of 1 g of powder of
1in 100 mL of acidic water−solution at pH = 2 has been
followed. After 2 h, the total degradation of 1has been
observed, going along with chromatic change of the aqueous
acidic medium to a light blue solution, after release of Ca2+
followed by inductively coupled plasma mass spectrometry
(ICP-MS, see Experimental Section and Figure S11)and
Cu2+ ions. To further investigate the structural stability in
aqueous media, we performed PXRD in acidic (pH = 3), pure
water, and basic aqueous media (pH = 11) by immersing
powder of 1in aqueous solutions for a given time (Figure
S9c−e). As shown in Figure S9c,d, the PXRD patterns of a
polycrystalline sample of 1show retention of crystallinity over
the range of pH studied. This confirmed the good structural
robustness of the material in water and its acidic lability.
Indeed, at pH = 3 (Figure S9e) and lower, the release of drug
can be accomplished through the degradation of the
biocompatible framework (see Figure S11).
This represents only an initial result to place 1among the
valuable candidates for drugs encapsulation and their further
release in acidic conditions, without any implication of
recovery process or toxic effects, thanks to its biocompatibility.
■CONCLUSIONS
Here, we have rationally designed a new biocompatible chiral
bioMOF. It represents a rare example of a MOF constructed
from nontoxic ligands and using biometals,
22
copper, and
calcium ions. An aspartic acid-based ligand has been used to
build a novel porous network, which shows the capability to
encapsulate dopamine and degrades under acidic gastric
physiological conditions. The use of coordinating units, built
by metal ions and organic linkers, of minimal toxicity should be
considered when constructing MOFs as platforms for drug
carriers or therapeutic agents. The results here presented of
dopamine hydrochloride loading as a drug model represent a
promising start for 1to act as a drug carrier in more realistic/
physiological conditions. These results represent a step forward
to efficiently exploit MOFs for the transport of chiral drugs, a
field of paramount importance, where MOFs have started to
show they can be game changers. Further work is currently
developed in our lab in this direction.
■EXPERIMENTAL SECTION
Materials. All chemicals were of reagent grade quality. They were
purchased from commercial sources and used as received.
Physical Techniques. Elemental (C, H, N) analyses were
performed at the Microanalytical Service of the Universitat de
València. FT-IR spectra were recorded on a PerkinElmer 882
spectrophotometer as KBr pellets. 1H NMR spectra were recorded
at room temperature on a Bruker AC 200 (200.1 MHz) spectrometer.
Thermogravimetric analysis (TGA) data were recorded on an SDT-
Q600 analyzer from TA Instruments. The temperature varied from
Figure 5. Viability of MCF7 and SkBr3 breast cancer cells upon
exposure to 5 μMofbioMOF 1was assessed by MTT assay and
expressed as a percentage of cells exposed to chemicals with respect to
vehicle treated cells.
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E

RT to 600 °C at a heating rate of 10 °C·min−1. Measurements were
carried out on samples in open platinum crucibles under a flow of air.
Preparation of H2Me2-(S,S)-aspartamox = Bis[(S)-
dimethylaspartate]oxalyl Diamide. The proligand was prepared
using the following synthetic procedure: First, under a N2atm, an
excess of thionyl chloride (13.10 mL, 180 mmol) was added dropwise,
under stirring at 0 °C on an ice bath, to a solution of (L)-aspartic acid
(7.99 g, 60 mmol) in 150 mL of MeOH. The resulting colorless
solution was refluxed for 6 h and kept under stirring overnight. Then,
the excess of thionyl chloride was distilled with MeOH (3 ×150 mL).
The reaction mixture was washed with acetone (150 mL) and diethyl
ether (100 mL) and further concentrated, under reduced pressure, to
afford the dimethyl ester derivative of the (L)-aspartic acid amino acid,
which was used in the next step without further purification. Second,
the resulting dimethyl ester derivative of the (L)-aspartic acid amino
acid (9.67 g, 60 mmol) was dissolved in 250 mL of dichloromethane
and charged with triethylamine (8.4 mL, 60 mmol). To the resulting
colorless reaction mixture was added dropwise another solution
containing oxalyl chloride (2.54 mL, 30.0 mmol) in dichloromethane
(50 mL) under stirring at 0 °C on an ice bath. The resulting solution
was stirred overnight. The small amount of white solid (Et3NHCl)
obtained was filtered off, and the resulting solution was concentrated
to dryness in a rotatory evaporator to afford a white solid, which was
suspended in tetrahydrofuran to extract the target proligand and
remove the remaining Et3NHCl and then further concentrated in a
rotatory evaporator and dried under vacuum. Yield: 10.16 g, 90%;
Anal. Calcd (%) for C14H20N2O10 (376.3): C 44.68, H 5.36, N 7.44;
found C 44.36, H 5.26, N 7.36; 1H NMR (CDCl3): 2.88 (dd, 2H;
CH2), 3.10 (dd, 2H; CH2), 3.73 (s, 3H; OCH3), 3.81 (s, 3H; OCH3),
4.86 (t, 2H; CH), 8.20 (d, 2H; NH from CONH). IR (KBr): ν=
1760, 1740, and 1650 cm−1(CO).
Preparation of (Me4N)2{Cu2[(S,S)-aspartamox](OH)2}·4H2O.
An aqueous solution (60 mL) of H2Me2-(S,S)-aspartamox (11.29 g,
30 mmol) was treated with a 25% methanolic solution of Me4NOH
(150 mmol). Another aqueous solution (35 mL) of CuCl2·2H2O
(10.23 g, 60 mmol) was then added dropwise while the reaction
mixture was stirred. The resulting deep green solution was filtered to
remove solid particles and then concentrated to a volume of ca. 10
mL in a rotary evaporator. The mixture was then allowed to stand at 0
°C on an ice bath for 15 min, and finally, it was filtered to afford a
green polycrystalline solid that was gently washed with acetone,
filtered off, and dried under vacuum. Yield: 12.31 g, 59%; Anal. Calcd
for C18H40Cu2N4O16 (695.62): C, 31.08; H, 5.80; N, 8.05%. Found:
C, 30.97; H, 5.73; N, 8.12%; IR (KBr): ν= 3641 cm−1(O-H), 2986
cm−1(C-H), 1708, 1643, and 1619 cm−1(CO).
Preparation of Ca5II{CuII10[(S,S)-aspartamox]5}·160H2O (1).
Well-shaped elongated prisms of 1appropriate for X-ray structural
analysis were obtained by slow diffusion in an H-shaped tube
Figure 6. (a) Concentration of dopamine hydrochloride in the soaked solution and (b) the adsorption amount in mg of drug versus time in 8.25
mg of polycrystalline powder of MOF, which has been soaked in a solution of dopamine hydrochloride at 4510 mg/L (V= 0.55 mL). Inset in (a)
shows the scheme of dopamine drug.
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F

containing aqueous solutions of stoichiometric amounts of
(Me4N)2{Cu2[(S,S)-aspartamox](OH)2}·4H2O (0.100 g, 0.1 mmol)
in one arm and CaCl2(0.011 g, 0.1 mmol) in the other. Anal. Calcd
for C50Cu10Ca5H350N10O210 (5289.11): C, 11.35; H, 6.67; N, 2.65%.
Found: C, 11.28; H, 7.05; N, 2.67%; IR (KBr): ν= 1602 cm−1(C
O).
Response of Ca5II{CuII10[(S,S)-aspartamox]5·160H2O (1) to
Gastric Low pH. 1 g of powder of 1has been treated with 100 mL of
acidic water solution at pH = 2. After 2 h has been observed the total
degradation of 1(see Figure S11).
X-ray Powder Diffraction Measurements. A fresh polycrystal-
line sample of 1was introduced into 0.5 mm borosilicate capillaries
prior to being mounted and aligned on a Bruker D8 Discover powder
diffractometer, using Cu Kαradiation (λ= 1.54056 Å). Five repeated
measurements were collected at room temperature (2θ=2−50°) for
each sample and merged in a single diffractogram. The simulated
powder pattern was calculated from single-crystal X-ray diffraction
data and processed by the Mercury program (Version 4.2.0)
37
provided by the Cambridge Crystallographic Data Centre.
Single-Crystal X-ray Diffraction. A crystal of 1was selected and
mounted on a MITIGEN holder in Paratone oil and then quickly
placed on a liquid nitrogen stream cooled at 90 K to avoid the
degradation upon dehydration. Diffraction data were collected on a
Bruker-Nonius X8APEXII CCD area detector diffractometer using
graphite-monochromated Mo-Kαradiation (λ= 0.71073 Å). The data
were processed through the SAINT reduction and SADABS
38
multi-
scan absorption software, and the structure was solved with the
SHELXS structure solution program, using the Patterson method.
The model was refined with version 2018/3 of SHELXL against F2on
all data by full-matrix least-squares.
39,40
All non-hydrogen atoms were refined anisotropically with the use
of restrains on geometrical (DFIX) and displacement parameters
(SIMU and DELU). Some additional restrains to make the
refinement more efficient have been applied; for instance, ADP
components have been restrained to be similar to other related atoms,
using SIMU 0.04 for disordered fragments or EADP for a group of
atoms of the ligands expected to have essentially similar ADPs. The
solvent molecules were disordered (some refined double positions
O27W, O28W, and O78W), and they have been only in part
modeled. The quite large channels featured by these MOF likely
account for that. In fact, only water molecules pseudo-coordinated to
copper and calcium metal ions have been modeled. Any attempt to
locate and model the highly disordered guest molecules in the pores
was unsuccessful.
For that reason, in 1, the contribution to the diffraction pattern
from the disordered water molecules situated in the voids was
subtracted from the observed data through the SQUEEZE method,
implemented in PLATON.
36
The total potential accessible voids
calculated from PLATON is 9548.6 Å3per unit cell which accounts
for 55.0% of the unit cell volume [17355.0 Å3]. SQUEEZE estimated
a total count of 4918 electrons per 8058.8 Å3of solvent accessible
volume in 1, which is in good agreement to 123 water molecules (Z=
4; H2O = 10e−; 4918e−/4 = 1229.5e−≈123H2O). This estimated
solvent amount must be added to the number of water molecules
modeled and surrounding Ca2+ that is 37 per formula, to give a final
formula of Ca5Cu10(aspartamox)5·160 H2O.
The hydrogen atoms of the ligand were set in calculated positions
and refined as riding atoms, whereas, for water molecules, they were
neither found nor calculated.
A summary of the crystallographic data and structure refinement
for the crystal structure is given in Table S1. CCDC reference number
is 2075709.
The final geometrical calculations on free voids and the graphical
manipulations were carried out with PLATON
36
implemented in
WinGX,
41,42
and CRYSTAL MAKER programs,
43
respectively.
Cell Cultures. MCF7 and SkBr3 breast cancer cells were
maintained in DMEM/F-12 and RPMI 1640, respectively, supple-
mented with 5% fetal bovine serum (FBS), 100 mg/mL penicillin/
streptomycin, and 2 mM L-glutamine (Life Technologies, Milan,
Italy).
HPLC-UV Analyses. The HPLC-UV analyses were performed by
means of a FractionLynx system from Waters (Milford, MA) working
in analytical mode. The instrument is equipped with a 2535
quaternary pump and a 2989 UV/visible detector. The analytical
column used for the chromatographic separation was a C18 reversed-
phase column, named Luna (250 ×4.6 mm, 5 μm, Phenomenex).
The injection volume was 20 μL of a suitably diluted sample coming
from solution in contact with MOF after 0, 1.5, 24, 48, and 120 h. The
elution was carried out with 0.1% formic acid in water (solvent A) and
methanol (solvent B) under gradient conditions. The gradient steps
were the following: from 100 to 92% A (0−8 min), from 92 to 20% A
(8−18 min), 20% A in isocratic for 2 min, from 20 to 80% A (20−24
min). Finally an isocratic flow (8 min) to equilibrate the system
before starting the new analysis was used. The total run time was 32
min, while the flow rate was set at 1 mL/min and the UV detector was
set at 280 nm. The concentration of the solution of dopamine
hydrochloride in contact with MOF was evaluated using an external
calibration curve gained by standard solutions ranging from 50 to 300
μg/mL. The experiment was performed in triplicate, and results are
reported as average values ±3 SD. Data are reported in Figures 6 and
S10.
ICP-MS Analyses. The Ca2+ concentrations during degradation at
pH = 2 were determined by utilizing an inductively coupled plasma-
mass spectrometer (ICP-MS iCAP TQ Thermo Fisher Scientific,
USA) equipped with a Peltier cooled high purity quartz baffled
cyclonic spray chamber, a concentric borosilicate glass nebulizer, a
wide 2.5 mm internal diameter quartz injector, a nickel sample, and
two skimmer cones with 1.1 and 0.5 mm diameter orifices,
respectively. The ICP torch was a demountable single piece quartz
torch. The samples were collected by a Thermo Scientific
Autosampler Housing with a peristaltic pump equipped with three-
stop flared PVC pump tubing. A multielement standard solution was
used to calibrate the instrument using different analytical concen-
trations. Ultrapure water (18.3 MΩcm, Arioso, Human Corporation,
Korea) was used for the aqueous solution preparation. Aliquots of 100
μL were taken for the determination of calcium concentrations at
fixed time intervals. Experiment was performed in triplicate, and
results are reported as average values ±3 SD. Data are reported in
Figure S11.
■ASSOCIATED CONTENT
*
sıSupporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c01701.
Additional preparations and physical characterization
data. Additional figures (Figures S1−S11). Crystallo-
graphic details and refinement for 1(Table S1) (PDF)
Accession Codes
CCDC 2075709 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif,orbyemailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■AUTHOR INFORMATION
Corresponding Authors
Jesus Ferrando Soria −Departament de Química Inorgànica,
Instituto de Ciencia Molecular (ICMOL), Universitat de
València, 46980 Paterna, València, Spain;
Email: jesus.ferrando@uv.es
Donatella Armentano −Dipartimento di Chimica e
Tecnologie Chimiche, Universitàdella Calabria, Rende
87036 Cosenza, Italy; orcid.org/0000-0002-8502-8074;
Email: donatella.armentano@unical.it
Inorganic Chemistry pubs.acs.org/IC Article
https://doi.org/10.1021/acs.inorgchem.1c01701
Inorg. Chem. XXXX, XXX, XXX−XXX
G

Emilio Pardo −Departament de Química Inorgànica, Instituto
de Ciencia Molecular (ICMOL), Universitat de València,
46980 Paterna, València, Spain; orcid.org/0000-0002-
1394-2553; Email: emilio.pardo@uv.es
Authors
Marta Mon −Departament de Química Inorgànica, Instituto
de Ciencia Molecular (ICMOL), Universitat de València,
46980 Paterna, València, Spain
Rosaria Bruno −Dipartimento di Chimica e Tecnologie
Chimiche, Universitàdella Calabria, Rende 87036 Cosenza,
Italy
Rosamaria Lappano −Dipartimento di Farmacia e Scienze
della Salute e della Nutrizione, Universitàdella Calabria,
Rende 87036 Cosenza, Italy
Marcello Maggiolini −Dipartimento di Farmacia e Scienze
della Salute e della Nutrizione, Universitàdella Calabria,
Rende 87036 Cosenza, Italy
Leonardo Di Donna −Dipartimento di Chimica e Tecnologie
Chimiche, Universitàdella Calabria, Rende 87036 Cosenza,
Italy; orcid.org/0000-0002-0869-9755
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.1c01701
Notes
The authors declare no competing financial interest.
■ACKNOWLEDGMENTS
This work was supported by the MINECO (Spain) (Projects
PID2019−104778GB−I00 and Excellence Unit “Maria de
Maeztu”CEX2019−000919−M) and the Ministero dell’Is-
truzione, dell’Universitàe della Ricerca (Italy). R.B. thanks
Fondazione CARIPLO (Project code: 2019−2090, “Economia
Circolare: ricerca per un futuro sostenibile”2019, MOCA) for
a postoctoral grant. Thanks are also extended to the “2019
Post-doctoral Junior Leader-Retaining Fellowship, la Caixa
Foundation (ID100010434 and fellowship code LCF/BQ/
PR19/11700011”and “Subvenciones concedidas a la ex-
celencia científica de juniors investigadores, SEJI/2020/034”
(J.F.S.). E.P. acknowledges the financial support of the
European Research Council under the European Union’s
Horizon 2020 research and innovation programme/ERC
Grant Agreement No. 814804, MOF-reactors. M.M. was
supported by Fondazione AIRC (IG 21322). R.L. and M.M.
acknowledge (i) the special award, namely, “Department of
Excellence 2018−2022”(Italian Law 232/2016) to the
Department of Pharmacy, Health and Nutritional Sciences of
the University of Calabria (Italy), (ii) the “Sistema Integrato di
Laboratori per L’Ambiente(SILA) PONa3_00341′”.
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I