An interpenetrated bioactive nonlinear optical MOF containing a coordinated quinolone-like drug and Zn(ii) for pH-responsive release

Article abstract of DOI:10.1039/c4dt02672a

A new interpenetrated bioactive nonlinear optical metal-organic framework [Zn₂(ppa)₂(1,3-bdc)(H₂O)] has been designed and synthesized, which shows both a high drug content of 63.9% and a good slow release effect in simulated physical conditions compared to other non-interpenetrated bioactive MOFs. It also shows a large powder second-harmonic generation (SHG) efficiency of 5.6 times that of KH₂PO₄ (particle size: 150-200 μm). This journal is

Full text of DOI:10.1039/c4dt02672a

Dalton
Transactions
View Article Online
View Journal | View Issue
PAPER
An interpenetrated bioactive nonlinear optical
MOF containing a coordinated quinolone-like drug
and Zn(II) for pH-responsive release†
Cite this: Dalton Trans., 2015, 44,
1800
Li-Na Duan, Qin-Qin Dang, Cai-Yun Han and Xian-Ming Zhang*
2 2 2
A new interpenetrated bioactive nonlinear optical metal–organic framework [Zn (ppa) (1,3-bdc)(H O)]
Received 23rd September 2014,
Accepted 13th November 2014
has been designed and synthesized, which shows both a high drug content of 63.9% and a good slow
release effect in simulated physical conditions compared to other non-interpenetrated bioactive MOFs. It
DOI: 10.1039/c4dt02672a
also shows a large powder second-harmonic generation (SHG) efficiency of 5.6 times that of KH
2 4
PO
www.rsc.org/dalton
(particle size: 150–200 μm).
active MOF” through direct coordination of the biomolecule
vitamin B3 with non-toxic metal Fe ions. However, the result-
Introduction
8
Metal–organic frameworks (MOFs) have captivated great atten- ing material degrades rapidly under physiological conditions.
tion from chemists due to their tremendous potential appli- Spencer demonstrated that deferiprone treatment for haemosi-
cations in gas storage, ion exchange, microelectronics, derosis can be included as a ligand in “bioactive MOFs” based
1
9
nonlinear optics, and catalysis. Besides, MOFs can be on zinc. Similarly, deferiprone is immediately released from
regarded as good candidates for drug delivery systems owing the MOF upon treatment with a PBS buffer. The burst release of
to their high drug loadings, biodegradability and versatile func- drug molecules from the two “bioactive MOFs” may be related
2
tionality. Since Ferey and colleagues first reported in 2006 that to their loose and non-interpenetrated structures. In addition,
MOFs could encapsulate drug molecules within the pores and second-order nonlinear optical (NLO) materials have attracted
3
release them slowly, some advances have been made in MOFs considerable research interest due to their important appli-
1
0
as drug delivery systems. Lin et al. have prepared a Pt-based cations in optoelectronic technologies. The second-harmonic
4
drug that has been used for creating a coordination framework.
generation (SHG) properties originate from the charge transfer
Horcajada and co-workers encapsulated ibuprofen within the as a result of the strong push–pull effect in donor–acceptor type
5
flexible microporous metal terephthalate MIL-53s. An et al. molecules. Longer bridging ligands have better conjugation
reported an important encapsulation and delivery of a cationic between the donor and the acceptor which can enhance the
drug (procainamide) from an anionic pillared zinc-adeninate molecular hyperpolarizability (β) of NLO materials. Herein, we
6
MOF in a phosphate buffer solution (PBS). In 2010, Horcajada, are developing another approach to build “bioactive MOFs”
Gref and co-workers have shown that porous nanoparticles of with controlled release properties, namely, an interpenetrated
iron carboxylate MOFs can adsorb and release several highly structure with the drug molecule directly coordinated to Zn(II).
challenging drugs, such as the antitumorals busulfan (Bu) and The interpenetration may enhance stability of this bioactive
doxorubicin (Doxo) and the antivirals azidothymidine tripho- MOF and avoid the fast release of drug molecules. This “bio-
7
sphate (AZT-Tp) and cidofovir (CDV). Until now, most of the active MOF” crystallizes in a noncentrosymmetric space group
drug delivery from MOFs has been achieved by impregnation of and has been found to be SHG active.
MOFs in a saturated solution of the drug, which strongly
depends on the porosity and volume and results in uncertain
encapsulation. MOFs are likely to degrade in the body, inevit-
ably raising additional toxic concerns. Serre and co-workers
developed another drug delivery approach to construct a “bio-
School of Chemistry and Material Science, Shanxi Normal University, Linfen, Shanxi
Province, China. E-mail: zhangxm@dns.sxnu.edu.cn
†
Electronic supplementary information (ESI) available. CCDC 1004090. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4dt02672a
1800 | Dalton Trans., 2015, 44, 1800–1804
This journal is © The Royal Society of Chemistry 2015

View Article Online
Dalton Transactions
Paper
Considering the above points, the therapeutic molecule The final solution was spectrophotometrically analyzed in the
pipemidic acid (Hppa) and low toxic 1,3-benzenedicarboxylate UV-vis region after reaching a stable state. UV-absorbance of
were used as ligands with Zn(II) to build “bioactive MOFs”. the standard solution was measured at a wavelength of 275 nm
Hppa is active against many pathogenic bacterial species (both as well for compound 1’s release of pipemidic acid. The
Gram-negative and Gram-positive) as a gyrase inhibitor and absorption maximum of 1,3-benzenedicarboxylate was at
has a very broad clinical application in the treatment and pre- 211 nm (Fig. S2 and S3, ESI†).
1
1
vention of respiratory, enteric, and urinary tract infections.
In a typical release experiment, compound 1 (10 mg) in a
Hppa with a large π-conjugated system can produce com- dialysis bag (cut-off molecular weight: 3500) was released
pounds with excellent SHG properties. Zinc is an essential under simulated physiological conditions of different pH
nutrient element for life in the required dosage range which (37 °C, bidimensional stirring at 100 rpm). The release media
1
2
can be used as an antibacterial growth agent. In nonlinear were simulated gastric fluid (SGF, 0.01 M HCl solution pH 2.0),
2
+
optically active MOFs, Zn is commonly used as a connecting simulated body fluid (SBF, NaH
2 4 2 4
PO –Na HPO buffer solution
point to avoid unwanted d–d transitions in the visible region. pH 7.4) and simulated intestinum crassum fluid (SIC, NaHCO
3
It is expected that integration of Hppa and Zn(II) as well as the buffer solution pH 8.3). The dispersion was dialyzed against
dicarboxylate ligand could lead to interpenetrated MOFs, 200 ml of the solution for 48 h. At each time point, a 1 ml
which can not only achieve the purpose of medical treatment aliquot of the solution was removed and replaced with fresh
but also show low toxicity values. In this work, we report a bio- solution. The experiment was done in triplicate. The aliquot
2 2 2 2
active MOF, namely [Zn (ppa) (1,3-bdc)(H O)]·2H O (1), which was then analyzed by UV-vis spectroscopy. Crystals of 1 were
shows both a high drug content and a good slow release effect ground and sieved into a series of distinct particle size ranges
in simulated physical conditions compared to other non-inter- of 25–40 μm and 63–80 μm. The tablets of 1 were prepared
penetrated bioactive MOFs. In addition, 1 with a large SHG under 15 MPa.
demonstrated its potential for application in the field of non-
linear optical materials.
Crystallographic studies
X-ray single-crystal diffraction data for 1 were collected on a
Bruker Smart APEX CCD diffractometer at 298(2) K using Mo
Experimental section
Materials and methods
Kα radiation (λ = 0.71073 Å). The program SAINT was used for
integration of the diffraction profiles, and the program
SADABS was used for absorption correction. The structure was
solved by a direct method using the SHELXS program of the
SHELXTL package and refined by the full-matrix least-squares
technique with SHELXL. All non-hydrogen atoms were refined
with anisotropic thermal parameters. Hydrogen atoms of the
organic ligand were generated theoretically onto the specific
carbon and refined isotropically with fixed thermal factors.
Hydrogen atoms of the water molecules could not be deter-
mined and are not included in the model. Further details for
structural analysis are summarized in Table S1, ESI† and
selected bond lengths and angles are shown in Table S2, ESI.†
UV-vis absorption was monitored with a Varian Cary 100 Scan
spectrophotometer. Scanning electron microscopy (SEM) was
performed using a JSM-7500F. X-ray powder diffraction (XRPD)
data were recorded using a Bruker D8 ADVANCE X-ray powder
diffractometer (CuKα, λ = 1.5418 Å). Photoluminescence analy-
sis was performed using an Edinburgh FLS920 luminescence
spectrometer. The FT-IR spectra were recorded from KBr
−
1
pellets in the range 400–4000 cm using a Perkin-Elmer Spec-
trum BX FT-IR spectrometer. Elemental analysis was per-
formed using a Vario EL-II elemental analyzer.
Syntheses
Second harmonic generation measurements
A mixture of Zn(OAC)
2
·2H
2
O (0.044 g, 0.2 mmol), Hppa
The measurements of the powder frequency-doubling effects
for 1 were carried out on the sieved samples by means of the
modified method of Kurtz and Perry. Crystals of 1 were
ground and sieved into a series of distinct particle size ranges
of 25–40, 40–63, 63–80, 80–125, and 125–150 μm, respectively,
which were pressed into a disk with a diameter of 8 mm that
was put between glass microscope slides and secured with tape
(
(
0.071 g, 0.2 mmol), 1,3-H bdc (0.033 g, 0.2 mmol), and NaOH
0.021 g, 0.5 mmol) in H O (8 mL) was sealed in a 25 mL
2
16
2
Teflon®-lined stainless steel container, which was heated at
30 °C for 3 d and then cooled down to room temperature at a
1
−
1
rate of 5 °C h . Yellow crystals of 1 were collected and washed
with distilled water and dried in air to give the product; yield,
6
4
8% based on Zn. Anal. calc. for C H Zn N O (1): C,
36 38 2 10 13
5.54; H, 4.03; N, 14.75. Found: C, 45.29; H, 4.52; N, 15.47%.
2 4
in a 1 mm thick aluminum holder. A powdered KH PO sample
used as the reference was sieved into the same size range.
Degradation tests
According to the molar ratio of compound 1, a mixture solu-
Results and discussion
Description of the structures
tion of 0.4 mM Zn(OAc) ·H O, 0.4 mM Hppa and 0.2 mM 1,3-
2
2
2
H bdc was prepared as a standard and the pH was controlled
by HCl (pH 2.0) before being diluted to volume. This change Compound 1 features 2D acentric structure constructed from
in UV absorbance was normalized for clarity in comparison. undulating 2D honeycomb networks via parallel 3-fold interpe-
This journal is © The Royal Society of Chemistry 2015
Dalton Trans., 2015, 44, 1800–1804 | 1801

View Article Online
Paper
Dalton Transactions
netration of (6,3) networks, in which the therapeutically active Thermal stability studies
pipemidic acid is directly coordinated to essential Zn(II). It
crystallizes in the monoclinic acentric space group Cc and the
asymmetric unit contains two Zn(II) ions, two ppa ligands, one
TGA curves of 1 in nitrogen at the rate of 10 °C min−1 were
obtained. There are three steps of weight loss (Fig. S7, ESI†).
The first weight loss is 5.23% in the temperature range of
1
,3-bdc and three water molecules (Fig. 1a). The Zn1 center
45–135 °C, which corresponds to the loss of non-coordinated
exhibits a distorted trigonal-bipyramidal coordination environ-
ment (Scheme S1, ESI†), defined by two carboxylate oxygen
atoms from 1,3-bdc, and two oxygen atoms and one nitrogen
atom from the ppa groups. The Zn2 center adopts a distorted
octahedral geometry, coordinated by two carboxylate oxygen
atoms from 1,3-bdc, two oxygen atoms and one nitrogen atom
from the ppa ligands, and one water molecule. The 1,3-bdc
ligand adopts a chelating bis(bidentate) coordination mode
while the ppa ligand acts as a tridentate bridged ligand to link
two Zn(II) ions. Based on these connections, Zn(II) ions are
and coordinated water molecules. Then the sample keeps rela-
tively stable in the temperature range of 135–330 °C. The
second weight loss is 43.37% at 330–495 °C and the last step is
33.36% in the temperature range of 495–680 °C, indicating the
complete deposition of the complex to form ZnO as a final
product. This conclusion is supported by the percentage of the
residues, which is in accordance with the calculated value
(
17.15%).
bridged by ppa and 1,3-bdc ligands alternately to generate a Degradation of 1 with different particle sizes under different
D open (6,3) layer with very large hexagonal rings (Fig. 1b). pH conditions
2
The size of the window is estimated from the distance between
two Zn(II) ions to be 21.6 Å × 24.1 Å. The layer is highly undu-
lating and the voids of a single layer are so large that they
allow two other undulating layers to penetrate in a parallel
manner, giving a 2D–2D 3-fold interpenetrating (6,3) network
Compound 1 contains a drug content as high as 63.9%, and
in vitro release experiments have been investigated in SGF, pH
2
.0, SBF, pH 7.4 and SIC, pH 8.3 respectively. Besides, the
release rate of drugs may be associated with the particle size of
, so we tested the degradation of 1 at different particle sizes
1
(Fig. 1c). According to the calculation of PLATON, 1 is nonpor-
including 25–40 μm, 63–80 μm and in pressed tablets, which
were characterized by SEM (Fig. S4, ESI†). The release profile
of Hppa is presented in Fig. 2 (particle size in the range
ous. The network of 1 is 2D–2D 3-fold interpenetrating (6,3)
nets (Fig. S1, ESI†).
25–40 μm). A progressive release was observed with no “burst
effect” under SGF, SBF and SIC respectively. Within 48 hours,
approximately 100% of Hppa was released in SGF and 1 had a
half life (t1/2) of ∼1.5 h. However, only 90.1% and 38.1% of the
drug was degraded in a comparative experiment in SBF and
SIC, respectively. 1 gave a t1/2 of ∼7 h and ∼18 h in SBF and
SIC. The release profile of 1 with a 63–80 μm particle size and
in pressed tablets is presented in Fig. S5 and S6.† The half life
of different particle sizes in SGF, SBF and SIC are summarized
in Table S1.† According to Table S1,† the smaller the particle
size, the faster the degradation. A possible reason for this may
be attributed to the specific surface area. In addition, regard-
less of the particle size of 1, the release rate of Hppa is fastest
in SGF compared with SBF and SIC. Compared with other bio-
8
9
active MOFs such as BioMIL-1 and deferiprone based MOFs
with a full release in two hours in PBS, the degradation of 1 is
Fig. 1 Coordination environments of Zn(II) (a), space filling view of a
single (b) and three-fold interpenetrated 2D networks in 1 (c). Symmetry
code in (a): b: 1/2 + x, 1/2 + z, 3/2 + z.
Fig. 2 pH-responsive release of pipemidic acid from compound 1 (par-
ticle size in the range 25–40 μm) under simulated physiological
conditions.
1802 | Dalton Trans., 2015, 44, 1800–1804
This journal is © The Royal Society of Chemistry 2015

View Article Online
Dalton Transactions
Paper
Fig. 5 Photoluminescence spectra of 1 and free Hppa ligand in solid
state at room temperature upon excitation 345 nm.
Fig. 3 XRPD patterns of 1 and the simulated XRPD from the single-
crystal X-ray structure.
1
6
using a pulsed Nd:YAG laser with a wavelength of 1064 nm.
As powder SHG efficiency has been shown to depend strongly
on particle size, materials were ground and sieved into distinct
particle size ranges (25–40, 40–63, 63–80, 80–125, 125–150 μm)
as illustrated in Fig. 4. 1 exhibits high transparency (above
significantly retarded, presumably due to the interpenetrated
structure of 1.
The release amount of Hppa increases with a decrease of
pH value. A possible reason is that both Zn(II) and protons are
Lewis acids and compete to combine with the ppa group. In a
solution of SGF (pH 2.0), protons have more opportunities to
combine with the ppa group compared to when in SBF and
SIC, which leads to full degradation of 1 and a large release
80%) in the range of 350–800 nm (Fig. S8, ESI†). The SHG
intensity for 1 is about 5.6 times that of technologically impor-
tant potassium dihydrogen phosphate (KDP) at a particle size
of 150–200 μm. Particle size vs. SHG efficiency data indicate
that 1 is type I phase-matchable. The large SHG efficiency may
be attributed to the longer bridging Hppa ligands which
exhibit better conjugation between the piperazine-N donor and
the carboxylate-acceptor, which is known to enhance the mole-
cular hyperpolarizability of inorganic second-order nonlinear
optical (NLO) chromophores.
1
3
rate. Compound 1 dissolved in SGF after full degradation,
while white insoluble solids formed after degradation in SBF
and SIC. These may be insoluble zinc phosphate and zinc car-
bonate respectively, according to the chemistry of zinc (Pour-
1
4
baix diagram).
The insoluble solids were further
characterized by XRPD (Fig. 3) and IR spectroscopy (Fig. S8†).
Interestingly, in the case of compound 1, the degradation pro-
ducts, zinc and 1,3-bdc, are endogenous, and show low toxicity
Photoluminescence properties
−
1
−1 15
10
values (LD (Zn) = 0.35 g kg , LD (1,3-bdc) = 10.4 g kg ).
Due to the excellent luminescence properties of d metal com-
5
0
50
Their non-toxic nature and unusually large drug capacity make plexes, the solid-state luminescence of the three compounds
1
7
them ideal candidates in the field of bioactive molecule was investigated at room temperature. It can be observed
delivery.
that intense emissions occur at 442 nm (Fig. 5, λex = 345 nm)
for 1. For free Hppa it was found that one weak emission at
5
06 nm could be observed. Therefore, the emission of 1 may
SHG properties
be attributable to ligand-to-metal charge transfer (LMCT). The
enhancement of the fluorescence emission intensity may be
attributed to the coordination of Hppa to metal ions increas-
ing the ligand conformation rigidity, which reduces the non-
radioactive decay of the intraligand excited state.
Second-harmonic generation (SHG) measurements of pow-
dered 1 were performed on a modified Kurtz-NLO system
Conclusions
In summary, we developed another approach to “bioactive
MOFs” with controlled degradation properties, namely, an
interpenetrated structure with the drug pipemidicate directly
coordinated to Zn(II). This bioactive MOF combined a high
drug content of 63.9% and a good release effect, which is suit-
able to be used as a drug delivery system. The interpenetration
enhanced the stability of this bioactive MOF and avoided fast
release of drug molecules. In addition, this acentric bioactive
Fig. 4 Particle size vs. SHG intensity for 1 showing type I phase-match- MOF shows a large SHG efficiency of 5.6 times that of techno-
ing curve.
logically important KDP.
This journal is © The Royal Society of Chemistry 2015
Dalton Trans., 2015, 44, 1800–1804 | 1803

View Article Online
Paper
Dalton Transactions
L. Cynober, S. Gil, G. Ferey, P. Couvreur and R. Gref, Nat.
Mater., 2010, 9, 172.
Acknowledgements
This work was supported by 973 Program 2012CB821701,
IRT1156, NSFC (20925101&21101102) and Shanxi Province
Science Foundation for Youths (2012021008-2).
8 S. R. Miller, D. Heurtaux, T. Baati, P. Horcajada,
J.-M. Greneche and C. Serre, Chem. Commun., 2010, 46,
4526.
9
A. D. Burrows, M. Jurcic, L. L. Keenan, R. A. Lane,
M. F. Mahon, M. R. Warren, H. Nowell, M. Paradowski and
J. Spencer, Chem. Commun., 2013, 49, 11260.
References
1
0 (a) H. Wu, H. Yu, S. Pan, Z. Huang, Z. Yang, X. Su and
K. R. Poeppelmeier, Angew. Chem., Int. Ed., 2013, 52, 3406;
(b) X. Xu, B.-P. Yang, C. Huang and J.-G. Mao, Inorg. Chem.,
2014, 53, 1756; (c) G. Zou, L. Huang, N. Ye, C. Lin,
W. Cheng and H. Huang, J. Am. Chem. Soc., 2013, 135,
18560.
1
(a) J. Lee, O. K. Farha, J. Roberts, K. A. Scheidt,
S. T. Nguyen and J. T. Hupp, Chem. Soc. Rev., 2009, 38,
1
450; (b) C. Wang, T. Zhang and W. Lin, Chem. Rev., 2012,
1
12, 1084; (c) S. Horiuchi, F. Kagawa, K. Hatahara,
K. Kobayashi, R. Kumai, Y. Murakami and Y. Tokura, Nat.
Commun., 2012, 3, 1308; (d) S. Yang, S. K. Callear, 11 L. Yang, D. Tao, X. Yang, Y. Li and Y. Guo, Chem. Pharm.
A. J. Ramirez-Cuesta, W. I. F. David, J. Sun, A. J. Blake,
Bull., 2003, 51, 494.
N. R. Champness and M. Schroder, Faraday Discuss., 2011, 12 A. S. Prasad, Mol. Med., 2008, 14, 353.
51, 19; (e) D. J. Tranchemontagne, K. S. Park, 13 (a) E. Fleige, M. A. Quadir and R. Haag, Adv. Drug Delivery
1
H. Furukawa, J. Eckert, C. B. Knobler and O. M. Yaghi,
J. Phys. Chem. C, 2012, 116, 13143.
S. Keskin and S. Kızılel, Ind. Eng. Chem. Res., 2011, 50, 1799.
P. Horcajada, C. Serre, M. Vallet-Regí, M. Sebban,
F. Taulelle and G. Férey, Angew. Chem., Int. Ed., 2006, 45,
Rev., 2012, 64, 866; (b) H. Zheng, C. Gao, B. Peng, M. Shu
and S. Che, J. Phys. Chem. C, 2011, 115, 7230; (c) C. Gao,
H. Zheng, L. Xing, M. Shu and S. Che, Chem. Mater., 2010,
22, 5437; (d) Y.-N. Xue, Z.-Z. Huang, J.-T. Zhang, M. Liu,
M. Zhang, S.-W. Huang and R.-X. Zhuo, Polymer, 2009, 50,
3706; (e) B.-L. Guo and Q.-Y. Gao, Carbohydr. Res., 2007,
342, 2416.
2
3
5
974.
4
5
W. J. Rieter, K. M. Pott, K. M. L. Taylor and W. Lin, J. Am.
Chem. Soc., 2008, 130, 11584.
P. Horcajada, C. Serre, G. Maurin, N. A. Ramsahye, F. Balas,
M. Vallet-Regí, M. Sebban, F. Taulelle and G. Férey, J. Am.
Chem. Soc., 2008, 130, 6774.
14 M. Pourbaix, Atlas of Electrochemical Equilibria in Aqueous
Solutions, National Association of Corrosion Engineers,
Houston, Tex., 2nd English edn, 1974.
15 http://www.drugfuture.com/toxic/q71-q610.html.
6
7
J. An, S. J. Geib and N. L. Rosi, J. Am. Chem. Soc., 2009, 131, 16 S. K. Kurtz and T. T. Perry, J. Appl. Phys., 1968, 39, 3798.
8
376.
17 (a) H.-T. Ye, C.-Y. Ren, G.-F. Hou, Y.-H. Yu, X. Xu, J.-S. Gao,
P.-F. Yan and S.-W. Ng, Cryst. Growth Des., 2014, 14, 3309;
(b) Y.-C. He, H.-M. Zhang, Y.-Y. Liu, Q.-Y. Zhai, Q.-T. Shen,
S.-Y. Song and J.-F. Ma, Cryst. Growth Des., 2014, 14, 3174.
P. Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie,
T. Baati, J. F. Eubank, D. Heurtaux, P. Clayette, C. Kreuz,
J.-S. Chang, Y. K. Hwang, V. Marsaud, P.-N. Bories,
1804 | Dalton Trans., 2015, 44, 1800–1804
This journal is © The Royal Society of Chemistry 2015