One-Pot Synthetic Approach toward Porphyrinatozinc and Heavy-Atom Involved Zr-NMOF and Its Application in Photodynamic Therapy

Article abstract of DOI:10.1021/acs.inorgchem.7b03204

Herein, we report an iodine-attached Zn(II)-porphyrinic dicarboxylic building block (ZnDTPP-I₂-2H, 1) that can be introduced into UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I₂ doped UiO-66 type nano metal-organic framework (NMOF) of ZnDTPP-I₂?UiO-66 (2). Compared to its homologous iodine-free NMOF of ZnDTPP?UiO-66 (4), ZnDTPP-I₂?UiO-66 (2) with heavy iodine atoms is a more effective nanosized photosensitizer for singlet oxygen generation under physiological conditions. As expected, 2 displayed a high photodynamic therapy efficacy for treatment of liver cancer cells in vitro.

Full text of DOI:10.1021/acs.inorgchem.7b03204

Article
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/IC
One-Pot Synthetic Approach toward Porphyrinatozinc and
Heavy-Atom Involved Zr-NMOF and Its Application in
Photodynamic Therapy
‡
‡
Le-Le Zhou, Qun Guan, Yan-An Li, Yang Zhou, Yu-Bin Xin, and Yu-Bin Dong*
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for
Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong
Normal University, Jinan 250014, P. R. China
*
S Supporting Information
ABSTRACT: Herein, we report an iodine-attached Zn(II)-porphyrinic
dicarboxylic building block (ZnDTPP-I -2H, 1) that can be introduced into
2
UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I2
doped UiO-66 type nano metal−organic framework (NMOF) of ZnDTPP-
I ⊂UiO-66 (2). Compared to its homologous iodine-free NMOF of
2
ZnDTPP⊂UiO-66 (4), ZnDTPP-I ⊂UiO-66 (2) with heavy iodine atoms is
2
a more effective nanosized photosensitizer for singlet oxygen generation
under physiological conditions. As expected, 2 displayed a high photodynamic
therapy efficacy for treatment of liver cancer cells in vitro.
INTRODUCTION
In this contribution, we report a defected UiO-66 type NPs
■
(
ZnDTPP-I ⊂UiO-66, 2) that contains iodine-attached Zn(II)-
2
Photodynamic therapy (PDT) is based on the energy-specific
light activation of photosensitizers (PS) to generate reactive
species, in particular, reactive oxygen species (ROS) such as
porphyrinic dicarboxylic linkage (ZnDTPP-I -2H, 1) via one-pot
2
synthetic approach. The generated ZnDTPP-I ⊂UiO-66 (2)
2
can be a highly effective nano PS in therapy for treatment of
1
cytotoxic singlet oxygen ( O ), which are highly toxic to
2
liver cancer cells in vitro.
1
diseased cells. Among various PSs, metalloporphyrins are widely
used as PS in PDT; their delivery efficiency to the diseased cells,
2
EXPERIMENTAL SECTION
however, is not very high due to their hydrophobic nature.
■
3
Nano metal−organic frameworks (NMOFs), as an emerging
Materials and Instrumentation. Pyrrole, benzaldehyde,
-iodobenzaldehyde, methyl 4-formylbenzoate, 2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone (DDQ), 1,3-diphenylisobenzofuran (DPBF), and
-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT)
4
class of porous materials, provide a unique platform for the effec-
tive loading of metalloporphyrinic moiety via in situ one-pot
synthetic approach. In this way, the metalloporphyrinic linkage
can be grafted on the MOF framework and, consequently, intro-
duced into periodic and porous MOF nanoparticles (NPs). For
3
were purchased from TCI Chemical Ind. Develop Co. Zirconium(IV)
chloride was purchased from Shanghai Macklin Biochemical Co., Ltd.
Trifluoroacetic acid (TFA), p-phthalic acid (PTA), zinc acetate, potas-
sium hydroxide, triethylamine, and acetic acid were purchased from
Sinopharm Chemical Reagent Co., Ltd. Dulbecco’s modified eagle
medium (DMEM), phosphate-buffered saline (PBS), Dulbecco’s
phosphate-buffered saline (DPBS), heat-inactivated new born calf serum,
and penicillin-streptomycin liquid were purchased from Invitrogen. All
reactants were reagent grade and were used as purchased without
further purification. The HepG2 cell lines were provided by Institute
of Basic Medicine, Shandong Academy of Medical Sciences. Ultrapure
water was prepared with an Aquapro system (18 MΩ). Infrared (IR)
samples were prepared as KBr pellets, and spectra were obtained in the
4
example, Zhou et al. reported that the tetraporphyrin linker,
which is comparable to the dimension of Zr6L12 assembly unit
in UiO-MOF, can be directly introduced in the framework via
reduced carboxyl-Zr connecting mode to generate the defected
6
5
UiO-66 frameworks.
However, the introduction of heavy atoms (Br or I) into a
photosensitizer is known to have an influence over the rates of
6
the intersystem crossing (ISC), the quantity of singlet oxygen
generation and, consequently, the photodynamic therapy effect.
So the incorporation of a heavy atom such as iodine into PS
and, furthermore, into MOF NPs, is very significant and could
meet therapeutic needs and profiles. In this way, the conven-
tional PS can be nanosized by means of NMOF supports;
consequently, highly efficient nano-PDT platform would be
−1
400−4000 cm range using a PerkinElmer 1600 FTIR spectrometer.
1
H NMR data were collected using an AM-300 spectrometer. Chem-
ical shifts are reported in δ relative to tetramethylsilane (TMS).
Received: December 20, 2017
7
built up.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Fluorescence spectra were obtained with FLS-920 Edinburgh Fluo-
rescence Spectrometer with a xenon lamp. The inductively coupled
plasma (ICP) measurements were obtained on Thermo Scientific iCAP
3129(w), 3056(w), 2943(w), 2840(w), 1726(s), 1606(m), 1553(m),
1474(w), 1432(m), 1400(m), 1347(w), 1307(w), 1266(m), 1220(w),
1211(w), 1178(m), 1112(m), 1097(m), 1062(w), 1036(m), 961(m),
843(s), 815(w), 797(m), 759(m), 730(m), 602(w), 506(w), 485(w).
HRMS [M + H] calcd forC H I N O : 983.0591, found: 983.628.
7000 ICP-OES. The scanning electron microscopy (SEM) micro-
graphs and energy-dispersive X-ray spectra (EDS) were recorded on a
Gemini Zeiss Supra TM scanning electron microscope. The X-ray
diffraction (XRD) experiments were obtained on a D8 ADVANCE
X-ray powder diffractometer with Cu Kα radiation (λ = 1.5405 Å).
Confocal fluorescence imaging studies were performed with a Leica
TCS SP8 confocal laser scanning microscopy (Leica Co., Ltd. Germany)
with an objective lens (×20). Mass spectrometry (MS) spectra were
obtained by Bruker maxis ultrahigh resolution-time-of-flight (TOF)
MS system. Elemental microanalyses (EA) were performed on Vario
EL cube elemental analyzer.
48
33 2
4
4
Anal. Calcd for C H I N O : C, 58.55; H, 3.48; N, 5.69, found: C,
48
34 2
4
4
58.81; H, 3.76; N, 5.63%.
5,15-Di(4-Methoxycarbonylphenyl)-10,20-bis(4-Iodophenyl)-
porphine Zinc. A mixture of 5,15-di(4-methoxycarbonylphenyl)-
10,20-bis(4-iodophenyl)porphine (151 mg, 0.154 mmol) and Zn(OAc)
2H O (269 mg, 1.23 mmol) in MeOH/CHCl (10 mL/40 mL) was
stirred overnight. The product was purified by column on Al (eluent,
methylene chloride) to generate purple crystalline solids (Yield, 98%).
·
2
2
3
O
3
2
1
H NMR (300 MHz, CDCl , ppm): 4.11 (s, 6 H), 7.92−8.46 (m, 12H),
3
−1
2
,2′-((4-Iodophenyl)methylene)bis(1H-pyrrole). A mixture of
8.81−8.85 (d, 8H). IR (KBr pellet cm ): 3108(w), 2950(w), 2798(w),
2072(w), 1805(w), 1723(m), 1703(s), 1606(m), 1520(w), 1480(w),
1433(w), 1386(w), 1337(w), 1311(w), 1271(m), 1204(w), 1115(w),
1072(w), 1060(w), 996(s), 887(w), 850(w), 822(w), 810(w), 794(m),
763(m), 718(s), 638(w), 570(w), 490(w), 456(w). HRMS [M + H]
calcd for C H I N O Zn: 1044.9726, found: 1044.498. Anal. Calcd
pyrrole (0.43 mol, 30 mL), 4-iodobenzaldehyde (2.737 g, 11.8 mmol),
and TFA (90 μL) was stirred in dark under N atmosphere for 15 min.
2
The product was purified by column on silica gel (methylene chloride/
petroleum ether = 1:1 (v/v) to provide the product as white crystalline
1
solids (Yield, 60%). H NMR (300 MHz, CDCl , ppm): 5.44 (s, 1H),
3
48 31 2
4
4
5
.91 (s, 2H), 6.18 (d, 2H), 6.73 (s, 2H), 6.9−7.7 (dd, 4H), 7.94 (s, 2H).
for C H I N O Zn: C, 55.01; H, 3.08; N, 5.35, found: C, 55.38; H,
48 32 2 4 4
−1
IR (KBr pellet cm ): 3328(s), 3128(w), 3097(w), 2857(w), 1553(w),
3.37; N, 5.18%.
5,15-Di(4-carboxyphenyl)-10,20-bis(4-Iodophenyl)porphine
Zinc (ZnDTPP-I -2H, 1). A mixture of 5,15-di(4-methoxycarbonyl-
1
1
7
486(m), 1456(w), 1399(m), 1311(w), 1282(w), 1259(w), 1188(w),
114(w), 1096(w), 1063(w), 1025(m), 1007(m), 885(w), 837(w),
80(m), 761(m), 731(m), 602(w), 581(w), 507(w). High-resolution
2
phenyl)-10,20-bis(4-iodophenyl)porphine zinc (151 mg, 0.144 mmol)
and aqueous KOH solution (7 wt %, 15 mL) in tetrahydrofuran
(THF; 35 mL) was stirred at 70 °C overnight. Then, the pH value of
(
HR) MS [M + H] calcd for C H IN : 349.0202, found: 349.0179.
15 14 2
Anal. Calcd for C H IN : C, 51.74; H, 3.76; N, 8.05, found: C, 51.93;
15
13
2
H, 3.32; N, 7.98%.
,15-Di(4-Methoxycarbonylphenyl)-10,20-bis(4-Iodophenyl)-
porphine. A mixture of methyl 4-formylbenzoate (0.22g, 1.35 mmol),
the system was adjusted to 1−2 by HCl (2 M) to provide purple
1
5
crystalline solids (Yield, 96%). H NMR (300 MHz, CDCl
3
, ppm):
7.90−8.20 (dd, 8H), 8.20−8.40 (dd, 8H), 8.79, 8.81 (d, 8H), 13.25
−1
2
,2′-((4-iodophenyl)methylene)bis(1H-pyrrole) (0.3 g, 0.86 mmol),
(s, 2H). IR (KBr pellet cm ): 2924(m), 1732(m), 1694(s), 1606(m),
1567(w), 1479(w), 1428(m), 1337(m), 1314(m), 1295(m), 1206(m),
1179(w), 1087(w), 998(s). 795(m), 767(w), 719(m). HRMS [M + H]
calcd for C H I N O Zn: 1016.9413, found: 1016.465. Anal. Calcd
and TFA (200 μL) in methylene chloride (120 mL) was stirred over-
night. After addition of DDQ (0.31 g, 1.35 mmol), the mixture was
stirred for additional 1 h. Then, the reaction was quenched by NEt3
46
27 2
4
4
(
4 mL). The product was purified by column on Al O (eluent, methylene
for C H I N O Zn: C, 54.17; H, 2.77; N, 5.49, found: C, 54.30; H,
2.70; N, 5.52%.
2
3
46 28 2 4 4
1
chloride) to generate purple crystalline solids (Yield, 14%). H NMR
(
(
300 MHz, CDCl , ppm): 2.87 (s, 2H), 4.12 (s, 6H), 7.92−8.46
Synthesis of ZnDTPP-I ⊂UiO-66 (2). A solution of ZrCl (19.6 mg,
3
2
4
−1
m, 12H), 8.81−8.85 (d, 8H). IR (KBr pellet cm ): 3322(s),
0.08 mmol), PTA (13.28 mg, 0.08 mmol), HOAc (120 μL), and
Scheme 1. Synthesis of 1
B
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
1
ZnDTPP-I -2H (1, 40 mg) in dimethylformamide (DMF; 3.2 mL)
absorbance at 414 nm due to the O produced by the porphyrin-
2
2
1
was heated at 120 °C under static conditions. After 24 h, the reaction
system was cooled to room temperature, and the precipitate was
isolated by centrifugation. The solid was washed by fresh DMF until
colorless and washed with acetone for additional three times. Finally,
induced porphyrin. To characterize the difference in the rate of O
produced by different samples, the ratio A/A of absorbance A and the
initial absorbance A at 414 nm at different irradiation times was cal-
culated and plotted as the ordinate for the irradiation time t. The same
concentrations of DMF dispersions or solutions of 1−4 without DPBF
were used as the references for UV−vis measurement.
2
0
0
−1
the solids were dried in air. IR (KBr pellet cm ): 3392 (s), 2929 (m),
1
1
4
661 (s), 1586 (s), 1505 (m), 1397 (s), 1254 (w), 1156 (w), 1098 (w),
061 (w), 1017 (w), 965 (w), 800 (w), 747 (m), 662 (m), 548 (w),
82 (w). Elemental analysis data (%): C, 43.55; H, 1.89; N, 0.09. ICP
Cell Imaging. The HepG2 cells were grown in DMEM (Invitrogen)
containing 10% heat-inactivated new born calf serum, 100 U/mL
penicillin, and 100 μg/mL streptomycin in an atmosphere of 5% CO2
and 95% air at 37 °C. For confocal fluorescence imaging, cells were
incubated in glass-bottom dishes for 24 h. Cells were incubated at 37 °C
analysis indicated that the Zn content was 0.09 wt %, corresponding to
doped 1.4 wt % of I-substituted Zn(II)-porphyrin.
Singlet Oxygen Generation Measurement. In vitro single
oxygen generation measurement was performed by modified method
using DPBF as capture agent. An amount of 2 mL of DMF containing
with 2 (10 μg/mL) in PBS for 1 h in an atmosphere of 5% CO and
2
95% air, then washed with PBS, and fluorescence images were
captured. Samples were excited with two lasers (405 nm for metal−
organic framework (MOF) and 514 nm for ZnDTPP-I ) and collected
with two groups of channels (450−500 nm for green channel and
630−680 nm for red channel), respectively.
1
00 μL of DPBF (1 mM) and corresponding photosensitizer samples
(1−4) was used in a quartz cuvette. Drums O for 1 min under a green
2
2
2
light-emitting diode (LED; ca. 540 nm, 20 mW/cm ) at room temper-
ature for 2 min. The absorbance intensity of DPBF at 414 nm in the
mixture was recorded at 15 s intervals. The rate of singlet oxygen gen-
eration was determined from the reduced absorbance intensity over
time. For the control experiments, DPBF absorption was also recorded
for negative comparison at the same conditions in the absence of
photosensitizer. DPBF was observed to have a significant decrease in
Phototoxicity. A suitable number of HepG2 cells were transferred
to a 96-well plate with a cell number of ∼5000 cells/well and
incubated overnight. After removal of the culture medium, the cells
were incubated with MOF dispersion (200 μL, concentration gradient
0−80 μg/mL) for 1 h. The dispersion was removed, DPBS (200 μL)
2
was added to each well, and the green LED lamp (20 mW/cm ) was
Scheme 2. Synthesis of 2
irradiated for 10 min. After removal of DPBS, DMEM high-glucose
medium (200 μL) was added to each well. After incubation for 24 h,
MTT (10 μL, 5 mg/mL) was added and left for 4 h. The supernatant
was removed by centrifugation. The precipitate was dissolved in dimethyl
sulfoxide (DMSO; 150 μL), and the absorbance at 490 nm was measured.
Dark Toxicity. A suitable number of HepG2 cells was transferred
to a 96-well plate with a cell number of ∼5000 cells/well and incubated
overnight. After removal of the culture medium, the cells were incubated
with MOF dispersion (200 μL, concentration gradient 0−80 μg/mL)
for 1 h. The dispersion was removed, and every well was washed once
with DPBS (200 μL). After removal of DPBS, DMEM high-glucose
medium (200 μL) was added to each well. After incubation for 24 h,
MTT (10 μL, 5 mg/mL) was added and left for 4 h. The supernatant
was removed by centrifugation. The precipitate was dissolved in
DMSO (150 μL), and the absorbance at 490 nm was measured.
RESULTS AND DISCUSSION
■
We hypothesized that the metalloporphyrinic moiety doped
UiO-66 NMOF ZnDTPP-I ⊂UiO-66 (2) could be the ideal PS
2
a
Scheme 3. Control Experiments for Demonstrating the Location of ZnDTPP-I Linkage in 2
2
a
The obtained samples were thoroughly washed with DMF and acetone to remove remaining porphyrinic species and dried in air. PXRD patterns of
the samples are identical to that of UiO-66 and 2, indicating the structural integrity and crystallinity of UiO-66 were maintained during the
experimental processes.
C
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
candidate for singlet oxygen generation and PDT in living cells.
(0.08 mmol), ZnDTPP-I -2H (1, 0.04 mmol), and HOAc
2
First, the PS of ZnDTPP-I is highly dispersed in the UiO-66
(120 μL) in DMF (3.2 mL) under solvothermal conditions.
The generated crystalline solids remained deep brown after
completely washing with DMF and acetone (Scheme 2), indicating
2
matrix and could effectively avoid the aggregation-caused
8
quenching (ACQ); second, the heavy atom introduction of
iodine would reasonably promote the ISC rate and, consequently,
enhance the singlet generation efficiency; third, the porous UiO-
framework could facilitate the generated singlet oxygen release;
that the ZnDTPP-I species existed in the defected MOF matrix
2
of 2 and that some positions where the Zr (PTA) moiety
6
12
belonged were occupied by the less coordinated but sizable
9
4
fourth, UiO-MOFs have low toxicity, and they can be easily
ZnDTPP-I linkages in the framework. The involved ZnDTPP-I
2
2
10
scaled down to nanoregimes (<200 nm), which allow them to
amount is 1.4 wt % (Zn, 0.09 wt %) based on the ICP mea-
surement. For further demonstrating the location of ZnDTPP-I2
in MOF, control experiments were designed and performed. As
be suitable for PDT in living cells.
The synthesis of ZnDTPP-I -2H (1) was shown in Scheme 1.
2
The zinc-free and iodine-substituted porphine of DTPP-I -2H
shown in Scheme 3, ZnDTPP-I content in the sample obtained
2
2
was obtained by the combination of methyl 4-formylbenzoate and
by impregnating method based on ZnDTPP-I -2H was only
2
2
, 2′-((4-iodophenyl)methylene)bis(1H-pyrrole) in the presence
0.06 wt %, indicating that the trace amount of ZnDTPP-I
resulted from a postsynthetic surface decoration. Meanwhile,
2
4
of TFA and DDQ in CH Cl . After coordination of Zn(OAc) and
2
2
2
hydrolysis with KOH, ZnDTPP-I -2H (1) was generated as purple
no ZnDTPP-I species was detected in the sample based on
2
2
crystalline solids by adjusting the pH value (1−2) with HCl (2M).
ZnDTPP-I -2Me, which was generated by the solvothermal
method used for synthesis of 2. On the one hand, the result
2
As shown in Scheme 2, ZnDTPP-I ⊂UiO-66 (2) was
2
prepared by the combination of ZrCl (0.08 mmol), PTA
indicated that −CO H was essential for the porphyrinic species
4
2
Figure 1. (a) PXRD patterns of 2 and UiO-66. (b) SEM image of 2. (c) DLS measurement. (d) N sorption isotherms of 2 and UiO-66. (e) SEM-EDX
2
image of 2. (f) PXRD patterns of 2 in PBS (pH = 7.4, normal cell microenvironments; and pH = 6.5, tumor cell microenvironment, 37 °C) after stability test.
D
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Figure 2. (a) Normalized UV−vis absorption spectra of 1 (5.4 μg/mL) and 2 (40 μg/mL) in DMF. (b) Steady-state fluorescence of UiO-66 (40 μg/mL)
and 2 upon excited at 405 nm. (c) Steady-state fluorescence of 1 (2.8 μg/mL) and 2 (200 μg/mL) upon irradiated at 540 nm. (d) Photostability of
2
1
(5.4 μg/mL) and 2 (40 μg/mL) in DMF solution under the green LED (ca. 540 nm, 20 mW/cm ) laser at different time.
introduction. On the other hand, the porphyrinic species could
and photoluminescence spectra (Figure 2). Figure 2a showed
that 1 has a Soret band at λmax = 426 nm and two Q bands at
559 and 599 nm that resulted from the enhanced molecular
symmetry caused by the involved Zn(II) center. 2 exhibits a
broadened and slightly blue-shifted Soret band at λmax = 420 nm
and four Q bands (520, 559, 597, and 650 nm) relative to 1,
which might be caused by the porphyrin ligand distortion with
lower molecular symmetry in the MOF matrix after its coor-
dination to Zr nodes.
not be encapsulated in UiO-66 pores to form a host−guest supra-
molecular complex. Thus, ZnDTPP-I in 2 should be located in
2
the UiO-66 matrix and coordinated to the Zr cluster cores.
6
The measured powder X-ray diffraction (PXRD) pattern of 2
is well consistent with that of pristine UiO-66, but it is quite
different from the starting material of ZnDTPP-I -2H (Figure 1a),
2
implying that the UiO-66 structural feature was well-maintained
after the ZnDTPP-I introduction. The scanning electron micros-
2
copy (SEM, Figure 1b) micrograph showed that the obtained
On the one hand, as indicated in Figure 2b, ZnDTPP-
ZnDTPP-I ⊂UiO-66 (2) NPs were uniformly distributed and
I ⊂UiO-66 (2) showed a fluorescence peak at ca. 457 nm upon
2
2
that their size was centered at ca. 110 nm in diameter, which is
further supported by the dynamic light scattering (DLS) measure-
ment (Figure 1c) and transmission electron microscope (TEM
image, Figure S1, Supporting Information) measurement.
405 nm UV light irradition, but the emission intensity is half-
fold weaker than that of pristine UiO-66 because of enhanced
ISC upon coordination of the ZnDTPP-I linkages to Zr(IV)
2
ions through the terminal carboxylate groups. On the other
hand, 2 also exhibited a 661 nm maximum emission peak upon
excited at 540 nm, which was attributed to the doped ZnDTPP-I2
moiety, but 1 showed basically no emission that might result
from the ACQ effect in solution. In addition, the photostability
of 1 and 2 was examined (Figure S2, Supporting Information).
As indicated in Figure 2d, no adsorption intensity changes were
detected in the UV−vis spectra of 1 and 2 during the given
time, indicating that 1 and 2 possessed the good photostability.
Considering the doped metalloporphyrin, the singlet oxygen
To examine the permanent porosity, N adsorption property
2
of 2 was measured at 77 K. As shown in Figure 1d, it displays a
typical type-I adsorption isotherm, featuring characteristics of
the microporous materials. The Brunauer−Emmett−Teller (BET)
2
surface area of 2 was found to be 901 m /g with a pore width
centered at 6.7 Å (Figure S1, Supporting Information). Com-
2
11
pared to its pristine UiO-66 (929 m /g), the surface area is
basically unchanged, which might result from the tiny amount
of doped ZnDTPP-I , so the highly porous nature of UiO-66
2
was well-maintained in 2. The EDS spectra indicated that the
dispersion of Zr and I species in 2 is uniform (Figure 1e), which
generation ability of ZnDTPP-I ⊂UiO-66 (2) NPs was examined,
2
12
in which DPBF was selected as the ROS indicator, and its
UV−vis adsorption spectra were monitored at different times.
As shown in Figure 3a, irradiation of the DPBF solution in the pre-
sence of 2 (40 μg/mL, equivalent to 0.56 μg/mL of ZnDTPP-I2)
caused a steady generation of singlet oxygen with a green LED
further confirmed the existence of ZnDTPP-I species in 2.
2
For PDT, stability of 2 in PBS (pH = 7.4 and 6.5, 37 °C) was
examined. PXRD patterns confirmed that 2 can retain its crys-
tallinity and structural integrity for 3 d under the normal and
tumor microenvironments (Figure 1f). This would ensure MOF
NPs to be intact during PDT treatment in cell culture medium.
2
(ca. 540 nm, 20 mW/cm ), and the decreasing adsorption band
of DPBF at 414 nm was observed.
However, the optical properties of ZnDTPP-I -2H (1) and
Compared to 1, the ZnDTPP-I -doped NMOF 2 showed a
2
2
ZnDTPP-I ⊂UiO-66 (2) were recorded by UV−vis absorption
much higher singlet oxygen generation efficiency (Figure 3b).
2
E
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Figure 3. Singlet oxygen generation ability of as-synthesiaed 1−4 NPs. (a) Time-dependent UV−vis absorption of DPBF/DMF (1 mM, 100 μL) at
2
4
14 nm with 2 (40 μg/mL) in PBS irradiated by green LED (ca. 540 nm, 20 mW/cm ) light source during 0−120 s. (b) Comparison of the decay
rate of DPBF, ZnDTPP-I -2H (1), ZnDTPP-I ⊂UiO-66 (2), ZnDTPP-2H (3), and ZnDTPP⊂UiO-66 (4). The UV−vis spectra were obtained by
irradiation of the DPBF/DMF solutions (1 mM) of 1 (5.4 μg/mL), 2 (40 μg/mL), 3 (4.1 μg/mL), and 4 (40 μg/mL) during 0−120 s, respectively.
2
2
2
The light source was green LED (540 nm, 20 mW/cm ).
For further confirmation of the heavy atom effect, photostable
ZnDTPP⊂UiO-66 (4) without iodine was also prepared by the
ZnDTPP-I species (λ = 514 nm). 2 was incubated with HepG2
2 ex
cells for 1 h, and we noticed that both green (450−500 nm)
and red (630−680 nm) luminescences were located in the
cytoplasm, indicating that NPs of 2 were able to pass across the
tumor cell membrane easily.
combination of ZrCl , PTA, and ZnDTPP-2H (3) under the
4
same reaction conditions (Supporting Information). As shown
in Figure 3b, a significant slower decay rate of DPBF absorption
at 414 nm for 4 was observed (Supporting Information), indicating
its singlet oxygen generation ability without heavy iodine spe-
cies is indeed lower than that of 2. On the basis of the above
In addition, the in vitro PDT treament of ZnDTPP-I ⊂UiO-
2
66 (2) was examined by using the standard MTT assays against
HepG2 cell line. The concentration range of 2 was 0−80 μg/mL.
2
observation, ZnDTPP-I -doped UiO-type NMOF 2 was chosen
The green LED (ca. 540 nm) with a power density of 20 mW/cm
2
to perform the in vitro test for photodynamic therapy on liver
cancer.
was used as the light source, and the irradiation time was 10 min.
On the one hand, as shown in Figure 5, compared to control
For examination of the cellular biocompatibility and mem-
brane permeability of ZnDTPP-I ⊂UiO-66 (2) NPs, cell imaging
2
experiments were performed (Figure 4). Human hepatoma
Figure 5. MTT assays for HepG2 cells incubated with ZnDTPP-
I ⊂UiO-66 (2) of different concentrations with (blue) and without
2
2
(red) of green LED irradiation (540 nm, 20 mW/cm ). The used concen-
trations of 2 were 5, 10, 20, 40, 60, and 80 μg/mL, which are, respectively,
equalvent to 0.07, 0.14, 0.28, 0.56, 0.84, and 1.12 μg/mL of ZnDTPP-
2
I2-2H (1). Green LED (ca. 540 nm) with a power density of 20 mW/cm
was chosen as the light source, and the irradiation time was 10 min.
Figure 4. HepG2 cells were incubated in glass-bottom dishes for 24 h.
Cells were incubated at 37 °C with 2 (10 μg/mL) in PBS for 1 h in an
group, cell viability of the treatment group was up to ca. 87%
without light irradiation with the concentration of 2 at 60 μg/mL
atmosphere of 5% CO , 95% air, then washed with PBS, and fluo-
2
rescence images were captured. Samples were excited with two lasers
(
ZnDTPP-I species content, 0.84 μg/mL), indicating that 2 is
(
405 nm for NMOF and 514 nm for the doped PS of ZnDTPP-I ) and
2
2
collected with two groups of channels (450−500 nm for green channel
and 630−680 nm for red channel), respectively.
biocompatible and almost no dark cytotoxicity in the
concentration range of 0−60 μg/mL (P > 0.05). On the other
hand, ZnDTPP-I ⊂UiO-66 (2) exhibited a dramatic decline in
2
cells (HepG2) were selected and visualized by using a green
channel for NMOF (λex = 405 nm) and a red channel for
cell viability after irradiation. Figure 5 showed that the cell
viability decreased to less than 50% for HepG2 when the
F
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
concentration of 2 was at 10 μg/mL (equivalent to 0.14 μg/mL
ACKNOWLEDGMENTS
■
2
of ZnDTPP-I ). Notably, with the increase of concentration of
2
We are grateful for financial support from NSFC (Grant Nos.
1671122, 21475078, and 21401118) and the Taishan Scholar’s
Construction Project.
2
to 40 μg/mL (equivalent to 0.56 μg/mL of ZnDTPP-I ), the
2
cell viability decreased to less than 25% for the HepG2 cells
after irradiation.
Recently, some very impressive works of porphyrinic NMOF-
based PSs for photodynamic therapy have been reported, which
are summrized in Table 1. Compared to the reported porphyrinic
REFERENCES
■
(1) (a) Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.;
Verma, S.; Pogue, B. W.; Hasan, T. Imaging and Photodynamic
Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev.
Table 1. Summary of Recent Typical Porphyrinic NMOF-
Based Photodynamic Therapy in Living Cells
2
010, 110, 2795−2838. (b) Pass, H. I. Photodynamic Therapy in
Oncology: Mechanisms and Clinical Use. J. Natl. Cancer Inst. 1993, 85,
443−456.
light source
cell
time
PS
MTT
2
sample
(mW/cm )
lines (min) (μM) (%)
ref
(
2) Garland, M. J.; Cassidy, C. M.; Woolfson, D.; Donnelly, R. F.
DBP-UiO
DBC-UiO
LED, 640 nm (100) SQ20B
LED, 640 nm (100) CT26
15
15
20
15
25 13
Designing Photosensitizers for Photodynamic Therapy: Strategies,
Challenges and Promising Developments. Future Med. Chem. 2009, 1,
25 14
20 15
30 16
25 17
6
(
67−691.
3) (a) Zhou, H.-C.; Long, J. R.; Yaghi, O. M. Introduction to
Metal−Organic Frameworks. Chem. Rev. 2012, 112, 673−674.
b) Rocca, J. D.; Liu, D.; Lin, W. Nanoscale Metal−Organic
Hf-PCN-224 laser, 661 nm (5)
PS@MOF laser, 660 nm (100) HeLa
Zr-PCN-224 laser, 420 nm; HeLa
30 nm (100)
4T1
30 101
15
30
3.5
1.75
(
6
Frameworks for Biomedical Imaging and Drug Delivery. Acc. Chem.
Res. 2011, 44, 957−968. (c) Huxford, R. C.; Rocca, J. D.; Lin, W.
Metal−Organic Frameworks as Potential Drug Carriers. Curr. Opin.
Chem. Biol. 2010, 14, 262−268. (d) Spokoyny, A. M.; Kim, D.;
Sumrein, A.; Mirkin, C. A. Infinite Coordination Polymer Nano- and
Microparticle Structures. Chem. Soc. Rev. 2009, 38, 1218−1227.
(e) Lin, W.; Rieter, W. J.; Taylor, K. M. L. Modular Synthesis of
Functional Nanoscale Coordination Polymers. Angew. Chem., Int. Ed.
TCPP/
BCDTE-
laser, 420 nm (100) B16
30
30
30 18
UiO-66
TBC-Hf
LED, 650 nm (100) CT26
15
10
38
25 19
25 20
DOX@
NPMOF
laser, 655 nm (300) HepG2 10
green LED, HepG2 10
ZnDTPP-
I2⊂UiO-66 540 nm (20)
0.55
25 this
work
2
(
009, 48, 650−658.
4) Sun, Y.; Sun, L.; Feng, D.; Zhou, H.-C. An In Situ One-Pot
NMOF-based PSs, the PDT treament of 2 in living cells met
low energy and convenient light source (green LED, 20 mW/cm ),
tiny PS amount (0.55 μM), and short irradiation time (10 min)
for less than 25% cell viability. So 2 herein is in a strong posi-
tion among the porphyrinic NMOF-based PDT materials.
2
Synthetic Approach towards Multivarite Zirconium MOFs. Angew.
Chem., Int. Ed. 2016, 55, 6471−6475.
(5) (a) Shearer, G. C.; Chavan, S.; Bordiga, S.; Svelle, S.; Olsbye, U.;
Lillerud, K. P. Defect Engineering: Tuning the Porosity and
Composition of the Metal−Organic Framework UiO-66 via
Modulated Synthesis. Chem. Mater. 2016, 28, 3749−3761. (b) Taka-
shima, Y.; Sato, Y.; Tsuruoka, T.; Akamatsu, K. Unusual Colorimetric
Change for Alkane Solvents with a Porous Coordination Framework.
Inorg. Chem. 2016, 55, 11617−11620.
CONCLUSIONS
In summary, we deisgned and synthesized a Zn(II)-porphyrinic
dicarboxylic species (ZnDTPP-I ) doped UiO-66-type NMOF
■
2
(6) (a) Gorman, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher, W.
ZnDTPP-I ⊂UiO-66 via one-pot synthetic approach. In this
2
M.; O’Shea, D. F. In Vitro Demonstration of the Heavy-Atom Effect
for Photodynamic Therapy. J. Am. Chem. Soc. 2004, 126, 10619−
way, the conventional PS of metalloporphyrin with heavy iodine
atoms can be successfully nanosized by means of NMOF
supports; consequently, highly efficient nano PDT platform
would be built. The generated NMOF herein can be a highly
effective nanophotosensitizer for photodynamic therapy of liver
cancer cells.
1
0631. (b) Goswami, P. P.; Syed, A.; Beck, L.; Albright, T. R.;
Mahoney, K. M.; Unash, R.; Smith, E. A.; Winter, A. H. BODIPY-
Derived Photoremovable Protecting Groups Unmasked with Green
Light. J. Am. Chem. Soc. 2015, 137, 3783−3786.
(7) Lismont, M.; Dreesen, L.; Wuttke, S. Metal-OrganicFramework
Nanoparticles in Photodynamic Therapy: Current Status and
Perspectives. Adv. Funct. Mater. 2017, 27, 1606314.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.inorgchem.7b03204.
■
S
(8) Mei, J.; Hong, Y.; Lam, J. W. Y.; Qin, A.; Tang, Y.; Tang, B. Z.
*
Aggregation-Induced Emission: The Whole Is More Brilliant than the
Parts. Adv. Mater. 2014, 26, 5429−5479.
̀
́ ́
(9) (a) Ruyra, A.; Yazdi, A.; Espin, J.; Carne-Sanchez, A.; Roher, N.;
Photostability of 1−4, additional characterization for 2,
synthesis and characterization of 3−4 (PDF)
Lorenzo, J.; Imaz, I.; Maspoch, D. Synthesis, Culture Medium Stability,
and In Vitro and In Vivo Zebrafish Embryo Toxicity of Metal−
Organic Framework Nanoparticles. Chem. - Eur. J. 2015, 21, 2508−
2
518. (b) Li, Y.-A.; Zhao, C.-W.; Zhu, N.-X.; Liu, Q.-K.; Chen, G.-J.;
AUTHOR INFORMATION
Corresponding Author
E-mail: yubindong@sdnu.edu.cn.
■
Liu, J.-B.; Zhao, X.-D.; Ma, J.-P.; Zhang, S.; Dong, Y.-B. Nanoscale
UiO-MOFs-based Luminescent Sensors for Highly Selective Detection
of Cysteine and Glutathione and Their Application in Bioimaging.
Chem. Commun. 2015, 51, 17672−17675.
(10) (a) Schaate, A.; Roy, P.; Godt, A.; Lippke, J.; Waltz, F.; Wiebcke,
M.; Behrens, P. Modulated Synthesis of Zr-Based Metal−Organic
Frameworks: From Nano to Single Crystals. Chem. - Eur. J. 2011, 17,
*
ORCID
Qun Guan: 0000-0002-5522-5106
Yu-Bin Dong: 0000-0002-9698-8863
Author Contributions
6
643−6651. (b) Li, Y.-A.; Zhao, X.-D.; Yin, H.-P.; Chen, G.-J.; Yang,
‡
These authors contributed equally.
S.; Dong, Y.-B. Drug-Loaded Nanoscale Metal-Organic Framework
with Tumor Targeting Agent for Highly Effective Hepatoma Therapy.
Chem. Commun. 2016, 52, 14113−14116.
Notes
The authors declare no competing financial interest.
G
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(
11) Shearer, G. C.; Chavan, S.; Ethiraj, J.; Vitillo, J. G.; Svelle, S.;
Olsbye, U.; Lamberti, C.; Bordiga, S.; Lillerud, K. P. Tuned to
Perfection: Ironing Out the Defects in Metal−Organic Framework
UiO-66. Chem. Mater. 2014, 26, 4068−4071.
(
12) Cheng, Y.; Samia, A. C.; Meyers, J. D.; Panagopoulos, I.; Fei, B.;
Burda, C. Highly Efficient Drug Delivery with Gold Nanoparticle
Vectors for in Vivo Photodynamic Therapy of Cancer. J. Am. Chem.
Soc. 2008, 130, 10643−10647.
(
13) Lu, K.; He, C.; Lin, W. Nanoscale Metal−Organic Framework
for Highly Effective Photodynamic Therapy of Resistant Head and
Neck Cancer. J. Am. Chem. Soc. 2014, 136, 16712−16715.
(
14) Lu, K.; He, C.; Lin, W. A Chlorin-Based Nanoscale Metal−
Organic Framework for Photodynamic Therapy of Colon Cancers. J.
Am. Chem. Soc. 2015, 137, 7600−7603.
(
15) Liu, J.; Yang, Y.; Zhu, W.; Yi, X.; Dong, Z.; Xu, X.; Chen, M.;
Yang, K.; Lu, G.; Jiang, L.; Liu, Z. Nanoscale Metal−Organic
Frameworks for Combined Photodynamic & Radiation Therapy in
Cancer Treatment. Biomaterials 2016, 97, 1−9.
(
16) Zhang, L.; Lei, J.; Ma, F.; Ling, P.; Liu, J.; Ju, H. A Porphyrin
Photosensitized Metal−Organic Framework for Cancer Cell Apoptosis
and Caspase Responsive Theranostics. Chem. Commun. 2015, 51,
1
(
0831−10834.
17) Park, J.; Jiang, Q.; Feng, D.; Mao, L.; Zhou, H.-C. Size-
Controlled Synthesis of Porphyrinic Metal−Organic Framework and
Functionalization for Targeted Photodynamic Therapy. J. Am. Chem.
Soc. 2016, 138, 3518−3525.
(
18) Park, J.; Jiang, Q.; Feng, D.; Zhou, H.-C. Controlled Generation
of Singlet Oxygen in Living Cells with Tunable Ratios of the
Photochromic Switch in Metal−Organic Frameworks. Angew. Chem.,
Int. Ed. 2016, 55, 7188−7193.
(
19) Lu, K.; He, C.; Guo, N.; Chan, C.; Ni, K.; Weichselbaum, R. R.;
Lin, W. Chlorin-Based Nanoscale Metal−Organic Framework
Systemically Rejects Colorectal Cancers via Synergistic Photodynamic
Therapy and Checkpoint Blockade Immunotherapy. J. Am. Chem. Soc.
2
(
016, 138, 12502−12510.
20) Liu, W.; Wang, Y.-M.; Li, Y.-H.; Cai, S.-J.; Yin, X.-B.; He, X.-W.;
Zhang, Y.-K. Fluorescent Imaging-Guided Chemotherapy-and-Photo-
dynamic Dual Therapy with Nanoscale Porphyrin Metal-Organic
Framework. Small 2017, 13, 1603459.
H
DOI: 10.1021/acs.inorgchem.7b03204
Inorg. Chem. XXXX, XXX, XXX−XXX