Titanium-Based Nanoscale Metal-Organic Framework for Type i Photodynamic Therapy

Article abstract of DOI:10.1021/jacs.8b13804

Nanoscale metal-organic frameworks (nMOFs) have shown great potential as nanophotosensitizers for photodynamic therapy (PDT) owing to their high photosensitizer loadings, facile diffusion of reactive oxygen species (ROSs) through their porous structures, and intrinsic biodegradability. The exploration of nMOFs in PDT, however, remains limited to an oxygen-dependent type II mechanism. Here we report the design of a new nMOF, Ti-TBP, composed of Ti-oxo chain secondary building units (SBUs) and photosensitizing 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) ligands, for hypoxia-tolerant type I PDT. Upon light irradiation, Ti-TBP not only sensitizes singlet oxygen production, but also transfers electrons from excited TBP? species to Ti⁴⁺-based SBUs to afford TBP^?+ ligands and Ti³⁺ centers, thus propagating the generation of superoxide, hydrogen peroxide, and hydroxyl radicals. By generating four distinct ROSs, Ti-TBP-mediated PDT elicits superb anticancer efficacy with >98% tumor regression and 60% cure rate.

Full text of DOI:10.1021/jacs.8b13804

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Communication
Titanium-Based Nanoscale Metal-Organic
Framework for Type I Photodynamic Therapy
Guangxu Lan, Kaiyuan Ni, Samuel S. Veroneau, Xuanyu Feng,
Geoffrey T Nash, Taokun Luo, Ziwan Xu, and Wenbin Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13804 • Publication Date (Web): 19 Feb 2019
Downloaded from http://pubs.acs.org on February 19, 2019
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Titanium-Based Nanoscale Metal-Organic Framework for Type
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Guangxu Lan, Kaiyuan Ni, Samuel S. Veroneau, Xuanyu Feng, Geoffrey T. Nash, Taokun Luo,
1
,1,2
Ziwan Xu, and Wenbin Lin*
1
2
Department of Chemistry and Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research,
The University of Chicago, Chicago, IL 60637, USA.
Supporting Information Placeholder
four distinct ROSs leads to superb anticancer efficacy with >98%
tumor regression and 60% cure rate.
ABSTRACT: Nanoscale metal-organic frameworks (nMOFs)
have shown great potential as nanophotosensitizers for
photodynamic therapy (PDT) owing to their high photosensitizer
loadings, facile diffusion of reactive oxygen species (ROSs)
through their porous structures, and intrinsic biodegradability. The
exploration of nMOFs in PDT, however, remains limited to an
oxygen-dependent type II mechanism. Here we report the design of
a new nMOF, Ti-TBP, composed of Ti-oxo chain second building
a
b
units
(SBUs)
and
photosensitizing
5,10,15,20-tetra(p-
benzoato)porphyrin (TBP) ligands, for hypoxia-tolerant type I PDT.
Upon light irradiation, Ti-TBP not only sensitizes singlet oxygen
production, but also transfers electrons from excited TBP* species
4
+
•+
3+
to Ti -based SBUs to afford TBP ligands and Ti centers, thus
propagating the generation of superoxide, hydrogen peroxide, and
hydroxyl radicals. By generating four distinct ROSs, Ti-TBP-
mediated PDT elicits superb anticancer efficacy with >98% tumor
regression and 60% cure rate.
1.1 nm
c
O2
e-
O2
With structural regularity and tunability, high porosity, and
intrinsic biodegradability, nanoscale metal-organic frameworks
-
O2
e-
e-
1
-9
(nMOFs) hold great potential in biomedical applications such as
1
0-16
photodynamic therapy (PDT).
In PDT, the structural and
compositional tunability of nMOFs allows the incorporation of a
variety of photosensitizers (PSs) to afford high PS loadings, while
the structural regularity of nMOFs keeps PSs isolated from each
other to avoid self-quenching. The high porosity of nMOFs
facilitates the diffusion of reactive oxygen species (ROSs) to exert
cytotoxic effects whereas the biodegradability of nMOFs alleviates
the concern of long-term toxicity.
H O
2
2
1O2
∙OH
Type I PDT
Type II PDT
Although PDT is an efficient anti-cancer treatment,17-20 it largely
relies upon an oxygen-dependent type II mechanism through
Figure 1. (a) Perspective view of Ti-(Ti·TBP) structure along the
(010) direction. (b) Coordination environments of Ti-oxo chain
SBUs. (c) Schematic showing both type I and type II PDT enabled
by Ti-TBP.
energy transfer from excited PSs to molecular oxygen (O
2
) to
). Therapeutic efficacy of type II
PDT is diminished in hypoxic environments found in many solid
1
21
generate singlet oxygen ( O
2
Violet square-shaped crystals of Ti-(Ti·TBP) were synthesized
2
2
tumors. In contrast, type I PDT is more hypoxia-tolerant by
generating cytotoxic radicals via electron transfer (ET) from
through a solvothermal reaction between TiCl
,10,15,20-tetra(p-benzoato)porphyrin (H TBP)
dimethylformamide with acetic acid (AcOH) as the modulator at
20 ºC for 7 days. Single crystal X-ray diffraction studies revealed
that the TBP ligands were metalated with Ti during crystal growth
and the Ti-coordinated TBP (Ti·TBP) ligands were linked by
infinite Ti-oxo chain SBUs to form a 3D framework of the new
4
·2THF and
5
4
in N,N-
23-25
excited PSs to O
2
and organic molecules.
We hypothesized that
the tunability of nMOFs can be harnessed to enable type I PDT.
Herein, we report the synthesis of a novel nMOF, Ti-TBP, and its
1
use in the first type I PDT mediated by nMOFs (Figure 1). In
1
addition to sensitizing O
2
generation, Ti-TBP produces superoxide
-
•
(O
2
), hydrogen peroxide (H
transferring electrons from excited TBP* species to Ti -based
SBUs to form TBP ligands and Ti centers. The generation of
2 2
O ), and hydroxyl radicals ( OH) via
1
8
22
4
2
6
9
topology with a point symbol of {4 .6 .8 .10}{4 .6}
Figure 1a and S2-3, SI). Each repeat unit of the Ti-oxo chain has
2 2 2
{4 .6 } {4}
4+
(
•+
3+
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five Ti4+ ions that are bridged by carboxylate groups from TBP or
acetate ligands and terminated by hydroxide groups (Figure 2a and
S1, SI). Negligible Cl was detected in Ti-(Ti·TBP) by X-ray
fluorescence (Cl:Ti = 0.0016:1), leading to a formula of
resolution TEM (HRTEM) imaging and fast Fourier transform
(FFT) patterns of Ti-TBP revealed a 4-fold symmetry, consistent
with the Ti-TBP structure projected in the (010) direction (Figure
2b). The distance between two adjacent lattice points in HRTEM
was measured to be ~1.6 nm, matching the distance between the
centers of two adjacent Ti-chain SBUs. Moreover, powder X-ray
diffraction (PXRD) pattern of Ti-TBP matched well with that
simulated from its idealized structure (Figure 2f).
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5
5
5
5
6
5 2 2 6 8
[Ti (Ti·TBP) (OAc) (OH) ](OAc) .
a
b
a
b
d
f
Ti-TBP
150
1
00
Hf-TBP
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
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0
50
Ti-TBP
Hf-TBP
H4TBP
H TBP
4
2
00 nm
10 nm
0
0
100
100
100
200
200
200
300
Time (s)
400
500
600
3400
100
2
3420
Field (G)
3440
3460
4
3
2
0
0
0
c
80
60
c
d
250
200
4
0
0
0
Ti-TBP
Hf-TBP
Ti-TBP
Hf-TBP
H4TBP
150
2
10
0
25
H4TBP
2
1
1
0
5
0
5
0
100
50
0
Ti-TBP Adsorption
Ti-TBP Desorption
0
300
Time (s)
400
500
600
0
200
300
Time (s)
400
500
600
e 40
GSH + Ti-TBP + light
GSH + Hf-TBP + light
2
00 nm
0
100
200
300
0.0
0.2
0.4
0.6
0.8
1.0
Length (nm)
30
Relative pressure (p/p0)
GSH + H TBP + light
4
e30
f
GSH + light
GSH + GSSG
2
0
0
0
Ti-TBP in PBS
Ti-TBP
Hf-TBP
Ti-TBP + H2O2 + light
Hf-TBP + H2O2 + light
H4TBP + H2O2 + light
Ti-TBP after irradiation
As-synthesized Ti-TBP
Simulated Ti-TBP
1
2
5
GSSG
GSH
2
0
0
300
Time (s)
400
500
600
0
4
6
8
10
Time (min)
15
Hf-TBP in PBS
1
-
Figure 3. Time-dependent O
and time-dependent H
upon light irradiation under oxygenated conditions. Time-
2 2
dependent enhanced OH generation from H O (e) and GSSG
generation from GSH (f) upon light irradiation under oxygen-free
conditions.
2
generation (a), O
O generation (c) and OH generation (d)
2 2
2
generation (b),
•
1
0
5
0
Hf-TBP after irradiation
As-synthesized Hf-TBP
Simulated Hf-TBP
•
10
100
Size (d. nm)
1000
5
10
15
20
2

4
+
Figure 2. TEM image (a), HRTEM image and FFT pattern (inset)
b), AFM topography and height profile (inset), and nitrogen
sorption isotherms (d) of Ti-TBP nMOFs. Number-averaged
diameters in water (e). PXRD patterns of Ti-TBP and Hf-TBP after
light irradiation for 15 min or soaking in 0.6 mM phosphate saline
buffer for 8 h (f).
We hypothesized that upon light irradiation, Ti centers in Ti-
TBP SBUs could be reduced to Ti centers (Ti → Ti , E = -0.50
V vs. NHE)26 via ET from the photo-excited TBP* to form TBP•+
3
+
4+
3+
(
,
1
in addition to energy transfer from TBP* to O to generate O (type
2
2
II PDT). The generated Ti3+ further reduces O to generate O
-
2
2
,
•
H O , and OH to enable type I PDT (Figure 1c). The Hf-TBP
2
2
4
+
3+
Lowering the reaction temperature to 80 ºC led to the synthesis
of Ti-TBP nMOF with non-metalated TBP ligands of the
composition [Ti (TBP) (OAc) (OH) ](OAc) . UV-Vis spectrum of
5 2 2 6 4
Ti-TBP showed four characteristic Q-bands for non-metalated TBP
ligands (Figure S5, SI). Thermogravimetric analysis of Ti-TBP
showed a weight loss of 82.9% in the 300 to 600 °C range,
matching the expected value of 82.4% (Figure S6, SI). By
combining inductively coupled plasma-mass spectrometry (ICP-
MS) analysis of Ti and UV-Vis analysis of TBP in digested Ti-TBP,
we determined the Ti:TBP ratio as 2.67 ± 0.16, which is close to
6
nMOF based on redox-inert Hf SBUs (Hf → Hf , E = -1.55 V
vs. NHE) was used as a control. PXRD, TEM, and DLS
measurements showed that crystalline Hf-TBP exhibited a diameter
of 100.0 ± 8.3 nm (Figure 1e, 1f, and S7, SI). Upon light irradiation,
Ti-TBP, Hf-TBP, and H
generation as determined by singlet oxygen sensor green (SOSG)
assays (Figure 3a). Only Ti-TBP enabled type I PDT by generating
2
a series of distinct ROSs, including O as determined by electron
paramagnetic resonance (EPR) with 5-tert-butoxycarbonyl-5-
methyl-1-pyrroline-N-oxide (BMPO) as a spin trap (Figure 3b),
2
7
1
4
TBP effected Type II PDT via
O
2
-
2
.5 expected for Ti-TBP but much lower than 3.5 expected for Ti-
H
2
O
2
•
as determined with a hydrogen peroxide assay kit (Figure 3c),
(
Ti·TBP).
and OH as determined by aminophenyl fluorescein (APF) assay
Figure 3d).
(
Transmission electron microscope (TEM) imaging of Ti-TBP
revealed square nanoplates with a diameter of ~150 nm (Figure 2a)
while atomic force microscopy (AFM) topography of Ti-TBP gave
a plate thickness of ~20 nm (Figure 2c and S4, SI). Dynamic light
scattering (DLS) measurements gave a diameter of 100.1 ± 4.0 nm
for Ti-TBP (Figure 2e). The porous structure of Ti-TBP was
confirmed by nitrogen sorption isotherms at 77 K with a Brunauer-
To demonstrate that Ti-TBP-enabled type I PDT can tolerate
hypoxia of solid tumors, we mimicked hypoxic cancer cell
environments with an oxygen-free aqueous solution containing
22
either H
2 2
O (in high concentration in hypoxic cancer cells) or
2
8
glutathione (GSH, a ubiquitous antioxidant in cells). Upon light
irradiation, Ti-TBP effectively reduced H O
2 2
generate highly cytotoxic OH, while Hf-TBP and H TBP or Ti-
through Ti3 to
+
2
•
Emmett-Teller (BET) surface area of 527.7 m /g (Figure 2d). High
4
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•
TBP without light irradiation did not enhance OH generation
We propose the mechanism of Ti-TBP enabled type I PDT in
Figure 4e and Section S4.4 (SI). Photoexcitation of TBP to TBP*
(ΔG , calculated from the emission peak of H TBP at 641 nm)
generates Ti and TBP via ET. The Ti centers generate O
•+
1
2
3
4
5
6
7
8
9
(Figure 3e and S8, SI). Furthermore, TBP elicited oxidative stress
by oxidizing GSH to glutathione disulfide (GSSG) as determined
by high performance liquid chromatograph (Figure 3f and S9, SI).
1
4
3
+
•+
3+
-
2
,
•
•+
a
100
b
2 2
H O , and OH whereas TBP oxidizes GSH to GSSG (Figure 4e).
0 g/mL
g/mL
2 g/mL
g = 2.001
g = 1.941
Ti-TBP - light
•+
1
The energy difference between TBP* to TBP (ΔG
2
= -ΔG
, determined by
·2THF). The Ti centers sequentially reduce O to
). The oxidation
), determined by cyclic
TBP, is sufficient to oxidize GSH to
1 3
– ΔG )
4+
3+
is enough to drive the reduction of Ti to Ti (ΔG
5
3
4
8
1
g/mL
g/mL
g/mL
2 g/mL
3+
the CV of TiCl
4
2
Ti-TBP - dark
50
-
•
32
generate O
potential of TBP•+ to TBP (ΔG
voltammogram (CV) of H
2 6 2 2 7 8
(ΔG ), H O (ΔG ), and OH (ΔG
20 g/mL
Hf-TBP - light
H4TBP - light
3
4
0
4
GSSG (ΔG ).
a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
4
4
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4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
00
625
650
675
700
2500
40
3000
3500
Field (G)
4000
4500
Wavelength (nm)
PBS
H TBP
Hf-TBP SOSG
Superoxide
Ti-TBP
4
c 80
d
3
0
0
60
2
4
0
0
0
10
0
Ti-TBP
Ti-TBP + benzoquinone
b
c
PBS
PBS
H
4
TBP
Hf-TBP 7-OHCCA
Ti-TBP
Ti-TBP
2
Ti-TBP
Ti-TBP + benzoquinone
0
100
200
300
400
500
600
0
100
200
300
400
500
600
Time (s)
Time (s)
e
H
4
TBP
TBP
TBP
Hf-TBP -H2AX
d
e
PBS
PBS
H
4
Hf-TBP DAPI
Annexin-V
PI
Ti-TBP
Ti-TBP
H
4
Hf-TBP Calcein AM
EtBr
Figure 4. (a) Emission spectra of 20 µM H
different amounts of TiCl ·2THF. (b) EPR spectra showed the
generation of Ti (g = 1.941) and TBP (g = 2.001) upon light
irradiation at 20 K. Time-dependent H
generation by Ti-TBP with or without benzoquinone upon light
irradiation. (e) Proposed mechanism for Ti-TBP enabled type I
PDT at pH 7.
4
TBP with addition of
4
3
+
•+
f 100
g 2.0
•
PBS (+)
O
2
(c) and OH (d)
H4TBP
Hf-TBP
2
H4TBP (+)
Hf-TBP (+)
80
Ti-TBP
1.5
60
40
20
0
Ti-TBP (+)
1
.0
.5
The mechanism of Ti-TBP-enabled type I PDT was next
investigated. H
with a Stern-Völmer constant (KSV) of 36.05 ± 0.67 mM ,
suggesting efficient ET from TBP* to Ti (Figure 4a and S10, SI).
Consistent with this, TBP luminescence was totally quenched in Ti-
TBP (Figure S11, SI). EPR spectra of Ti-TBP upon light irradiation
showed a sharp peak with a g-value of 2.001 that is attributable to
0
4 4
TBP luminescence was quenched by TiCl ·2THF
-1
0.0
0
20
40
60
80
100
0
2
4
6
8
10 12 14 16 18 20
4
+
Concentration (M)
Day post tumor inoculation
1
-
Figure 5. (a) Detection of O
2
(green) and O
2
(red) generation by
SOSG and a superoxide kit. Green and red florescence merged as
yellow florescence. (b) Coumarin-3-carboxylic acid assay showed
•+29
•
TBP
and a weak broad peak with a g-value of 1.941 that is
OH generation via fluorescence of generated 7-OH coumarin-3-
3+
30
assignable to Ti species (Figure 4b). No EPR signals were
observed for Ti-TBP in dark, and only faint EPR signals
corresponding to TBP were observed in Hf-TBP and H
light irradiation. The EPR results thus directly prove ET in Ti-TBP.
To understand Ti -mediated ROS generation, O
carboxylic acid (blue). (c) -H AX assays showed DNA DSBs.
2
Scale bar = 20 µm. (d) Annexin-V assay probed apoptotic cell death
process. DAPI (blue), FITC-Annexin-V (green) and PI (red)
indicate nucleus, apoptotic and dead cells, respectively. (e) Live
and dead cell assay demonstrated cell killing effect. Calcein AM
(green) and Ethidium Bromide (EtBr, red) dye indicate live and
dead cell, respectively. Scale bar = 50 µm except in (c). (f) MTS
assay showed anti-cancer effect in CT26 cells. (g) In vivo anti-
cancer effect on CT26 tumor-bearing BALB/c mice. N = 5. Black
and red arrows refer to intratumoral injection and light irradiation,
respectively.
•+
4
TBP upon
3
+
-
2
was scavenged
by benzoquinone to evaluate its influence on other ROSs (Figure
31
1
S12, SI).
proportion as the emission of H
to luminescence quenching by benzoquinone. Negligible amounts
of H O and OH were detected in the presence of benzoquinone
2 2
2 2
Figure 3c-d), demonstrating that both H O and OH are generated
O
2
generation of Ti-TBP decreased at the same
4
TBP (Figure S13 and S14, SI) due
•
•
(
-
3+
2
from O . We have thus shown that Ti can propagate the
generation of O , H O , and OH under light irradiation.
2 2 2
The cytotoxicity of Ti-TBP-mediated PDT was investigated in
vitro in CT26 cells. ICP-MS analysis demonstrated efficient uptake
-
•
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of Ti-TBP and Hf-TBP by CT26 cells (Figure S17, SI). Although
We thank Dr. Alexander Filatov for help with single crystal
refinement, Vlad Kamysbayev for help with X-ray fluorescence,
and Zhe Li for help with CV study. We acknowledge the National
Cancer Institute (U01-CA198989 and 1R01CA216436) and the
University of Chicago Medicine Comprehensive Cancer Center
(NIH CCSG: P30 CA014599) for funding support. Single crystal
diffraction studies were performed at ChemMatCARS, APS, ANL.
NSF's ChemMatCARS Sector 15 is principally supported by the
Divisions of Chemistry (CHE) and Materials Research (DMR),
National Science Foundation, under grant number NSF/CHE-
1346572. Use of the Advanced Photon Source, an Office of
Science User Facility operated for the U.S. Department of Energy
(DOE) Office of Science by Argonne National Laboratory, was
supported by the U.S. DOE under Contract No. DE-AC02-
1
-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
4
TBP, Hf-TBP, and Ti-TBP can all generate O
2 2
, O was only
detected in cells treated with Ti-TBP (Figure 5a and S18, SI). The
•
•
in vitro generation of OH was verified by direct OH detection via
coumarin-3-carboxylic acid assay (Figure 5b and S19, SI) and by
DNA double strand break (DSB) quantification with -H2AX assay
•
(
Figure 5c and S20, SI), both of which showed that OH was only
detected in Ti-TBP treated cells. Confocal imaging and flow
cytometry using an Annexin V/dead cell apoptosis kit showed that
significant numbers of cells underwent apoptosis when treated with
Ti-TBP (Figure 5d and S21-22, SI). MTS assay and live/dead cell
confocal microscopic images showed that Ti-TBP outperformed
Hf-TBP with IC50 values of 3.4 ± 0. 7 and 7.8 ± 2.4 µM,
respectively (Figure 5e-f, and S23-24, SI).
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6CH11357.
The therapeutic effects of Ti-TBP-mediated PDT were next
evaluated in vivo on a colorectal adenocarcinoma model of CT26-
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