Nanoscale metal-organic framework for highly effective photodynamic therapy of resistant head and neck cancer

Article abstract of DOI:10.1021/ja508679h

Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species (e.g., ¹O₂). Here we report the rational design of a Hf-porphyrin nanoscale metal-organic framework, DBP-UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP-UiO efficiently generates ¹O₂ owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile ¹O₂ diffusion through porous DBP-UiO nanoplates. Consequently, DBP-UiO displayed greatly enhanced PDT efficacy both in vitro and in vivo, leading to complete tumor eradication in half of the mice receiving a single DBP-UiO dose and a single light exposure. NMOFs thus represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic.

Full text of DOI:10.1021/ja508679h

Communication
pubs.acs.org/JACS
Nanoscale Metal−Organic Framework for Highly Effective
Photodynamic Therapy of Resistant Head and Neck Cancer
Kuangda Lu,† Chunbai He,† and Wenbin Lin*
Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States
S
* Supporting Information
or material-based PDT and photothermal agents to cancers; and
in some cases, encouraging clinical data are emerging.6
ABSTRACT: Photodynamic therapy (PDT) is an
effective anticancer procedure that relies on tumor
localization of a photosensitizer followed by light
activation to generate cytotoxic reactive oxygen species
Nanoscale metal−organic frameworks (NMOFs), constructed
from metal ion/ion clusters and organic bridging ligands, have
recently emerged as a promising nanocarrier platform for
therapeutic and imaging agents.7 Compared to other nano-
carriers, NMOFs combine many beneficial features into a single
delivery platform, including tunable chemical compositions and
crystalline structures; high porosity; and biodegradability. For
example, we used a NMOF to deliver both cisplatin (in the
pores) and siRNAs (on the surface) to overcome drug resistance
in ovarian cancer,7j and more recently, we demonstrated real-
time intracellular pH sensing in live cells with a fluorescent
NMOF by taking advantage of its crystalline and porous
structure.8
Here we report the design of a Hf−porphyrin NMOF as a
highly effective PS for PDT of resistant head and neck cancer.
Although porphyrin-based MOFs have been intensively studied,9
the delivery of PDT agents using porphyrin-based NMOFs has
not been realized. We hypothesized that the incorporation of a
porphyrin-derived bridging ligand into a robust and porous UiO
NMOF structure with proper morphologies and dimensions
would have several advantages over existing nanoparticle PDT
agents: first, the PS molecules are well-isolated in the framework
to avoid aggregation and self-quenching of the excited states;
second, coordination of porphyrin ligands to heavy Hf centers via
the carboxylate groups can promote intersystem crossing to
enhance ROS generation efficiency; third, the porous NMOF
structure provides a pathway for facile diffusion of ROS (such as
1O2) out of the NMOF interior to exert their cytotoxic effects on
cancer cells. In this NMOF design, an unprecedentedly high PS
loading can be achieved to enable highly effective PDT of
difficult-to-treat cancers.
1
(e.g., O2). Here we report the rational design of a Hf−
porphyrin nanoscale metal−organic framework, DBP−
UiO, as an exceptionally effective photosensitizer for PDT
of resistant head and neck cancer. DBP−UiO efficiently
1
generates O2 owing to site isolation of porphyrin ligands,
enhanced intersystem crossing by heavy Hf centers, and
facile 1O2 diffusion through porous DBP−UiO nanoplates.
Consequently, DBP−UiO displayed greatly enhanced
PDT efficacy both in vitro and in vivo, leading to complete
tumor eradication in half of the mice receiving a single
DBP−UiO dose and a single light exposure. NMOFs thus
represent a new class of highly potent PDT agents and
hold great promise in treating resistant cancers in the
clinic.
hotodynamic therapy (PDT) is a phototherapy that
Pcombines three nontoxic components, a photosensitizer
(PS), a light source, and tissue oxygen, to cause toxicity to
malignant and other diseased cells.1 The mechanism of PDT
involves energy transfer from the light-excited PS to oxygen and
other molecules in the tissue to generate reactive oxygen species
(ROS), particularly, singlet oxygen (1O2), which induces cellular
toxicity.1,2 PDT can lead to localized destruction of diseased
tissues via selective uptake of the PS and/or local exposure to
light, providing a minimally invasive cancer therapy. The
application of PDT in cancer treatment dates back to 1970s
when hematoporphyrin derivatives were studied for PDT
efficacy in vivo,1 and the first PDT agent photofrin was approved
for clinical use in 1993. Most clinically used PSs are from the
porphyrin family, with a few other dyes emerging as efficient PSs
in recent years.3
The new porphyrin derivative, 5,15-di(p-benzoato)porphyrin
(H2DBP), was synthesized by a condensation reaction between
4-(methoxycarbonyl)benzaldehyde and dipyrrylmethane, and
1
characterized by H and 13C NMR spectroscopy and mass
spectrometry (Figures S3−S5, Supporting Information [SI]).
The linearly aligned dicarboxylate groups of the DBP ligand
allow the construction of a DBP−UiO NMOF with the
framework formula of Hf6(μ3-O)4(μ3-OH)4(DBP)6. DBP−
UiO was synthesized by a solvothermal reaction between
HfCl4 and H2DBP in N,N-dimethylformamide (DMF) at 80
°C (Scheme 1). The resulting dark purple powder was washed
with copious amounts of DMF, 1% triethylamine in ethanol (v/
Selective localization of PSs in tumors is critical for effective
PDT. However, many PSs are hydrophobic in nature, which not
only leads to insufficient tumor localization but also causes PS
aggregation to diminish the PDT efficacy.4 Significant synthetic
modifications are thus needed to render these PSs effective PDT
agents in vivo. An alternative approach is to use nanocarriers to
selectively deliver therapeutic or PDT agents to tumors via the
enhanced permeation and retention (EPR) effect and some
times via active tumor targeting with ligands that bind to
overexpressed receptors in cancers.4,5 Indeed, a number of
nanoparticle platforms have been developed to deliver molecule-
Received: August 22, 2014
© XXXX American Chemical Society
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Communication
(SBUs) and DBP bridging ligands.10 DBP−UiO has a very
open framework structure with triangular channels of 1.6 nm in
dimensions as well as octahedral and tetrahedral cavities of 2.8
and 2.0 nm in dimensions, respectively.
Scheme 1. Synthesis of Hf−DBP NMOF and the Schematic
Description of Singlet Oxygen Generation Process
DBP−UiO particles display a plate morphology by trans-
mission electron microscopy (TEM) (Figure 1b and Figure S7,
SI). Nitrogen adsorption measurements gave a BET surface area
of 558 m2/g for DBP−UiO (Figure S8, SI). The composition of
DBP−UiO was confirmed by thermogravimetric analysis (Figure
S9, SI) and inductively coupled plasma−mass spectrometry
(ICP−MS), giving DBP loading of 77 wt % (calcd 73%) and Hf
content of 24.3% (calcd 23.7%), respectively. These results also
indicate that DBP ligands do not coordinate to Hf4+ ions via
nitrogen atoms during the UiO synthesis (the Hf content would
have been 37.2% if all DBP ligands were metalated).
v), and ethanol successively before being dispersed in ethanol as a
stock suspension.
Individual SBUs are clearly visible in high-resolution TEM
images of DBP−UiO (Figure 1c). The distances between SBUs
are measured to be approximately 2.7 nm (Figure S10, SI), which
are consistent with the calculated distances of 2.77 nm based on
the X-ray structure model. Fast Fourier transform (FFT) of the
high-resolution TEM image displays a 3-fold symmetry for the
nanoplates (Figure 1d), consistent with the cubic crystal system
of the DBP−UiO. The dimensions of the nanoplates are
measured to be ∼100 nm in diameter and ∼10 nm in thickness.
Such thin plates consist of only 4−5 sets of (111) packing layer
(d111 = 2.2 nm). Dynamic light scattering (DLS) measurements
gave an average diameter of 76.3 nm for the particles (Figure S11,
SI). Notably, the nanoplate morphology is particularly advanta-
geous for generating ROS for PDT. The diffusion length of 1O2 is
no more than 90−120 nm in aqueous environment11 and was
estimated to be 20−220 nm inside cells.12 Therefore, the
nanoplates as thin as 10 nm in thickness are ideally suited for
transporting 1O2 from the NMOF interior to the cell cytoplasm
to exert cytotoxic effects.
Numerous attempts failed to grow DBP−UiO crystals suitable
for single-crystal X-ray diffraction. Fortunately, we have
determined the single crystal structure of an analogue of
DBP−UiO, Zr6(μ3-O)4(μ3-OH)4(Zn−DPDBP)6 (Zn−
DPDBP−UiO, DPDBP is 5,15-di(p-benzoato)-10,20-diphenyl-
porphyrin and has the same length as DBP; Table S1 and Figure
S6, SI), whose powder X-ray diffraction (PXRD) pattern is
essentially the same as that of DBP−UiO (Figure 1a). DBP−UiO
thus adopts a UiO-type MOF structure that is built from 12-
connected Hf6(μ3-O)4(μ3-OH)4 secondary building units
The UiO framework was recently shown to be stable in
aqueous solution.7j,10 DBP−UiO was incubated in RPMI 1640
cell culture medium for 12 h to determine its stability in
physiologically relevant media. TEM images showed an
unaltered morphology of the nanoplates, and FFT proved that
the crystalline structure of DBP−UiO remained intact (Figures
1e,f and S12, SI). The PXRD patterns of the NMOF samples
before and after incubation in RPMI 1640 medium are identical
(Figure 1a), further confirming structural stability of DBP−UiO
in physiological environments.
The UV−visible absorption spectra of H2DBP and DBP−UiO
in phosphate buffer saline (PBS) buffers (pH = 7.4) are
compared in Figure 2a. H2DBP shows a Soret band at 402 nm
and four Q-bands at 505, 540, 566, and 619 nm. The extinction
coefficients of H2DBP at 402 and 619 nm are 2.2 × 105 and 1.7 ×
103 M−1 cm−1, respectively (Figures S13 and 14, SI). DBP−UiO
shows slight red shifts for all Q-bands, with the peaks appearing at
510, 544, 579, and 634 nm. The red-shifts probably result from
the coordination of the carboxylate groups of DBP ligands to
Hf4+ centers. The presence of four Q-bands and their red shifts
further support the presence of free-base porphyrin ligands in
DBP−UiO. The Soret band of DBP−UiO is significantly
broadened, presumably due to inequivalent ligand environments
in thin nanoplates as well as potential framework distortion in
thin MOF structures.
Figure 1. Morphology and structure of DBP−UiO. (a) PXRD patterns
of Zn−DPDBP−UiO, DBP−UiO, and DBP−UiO after incubating in
RPMI 1640 cell culture medium for 12 h. (b) TEM image of DBP−UiO
showing nanoplate morphology; high-resolution TEM images of DBP−
UiO samples before (c) and after (e) cell-medium cultivation, and their
fast Fourier transform patterns (d,f), respectively.
Singlet oxygen generation efficiencies of H2DBP and DBP−
UiO were determined using Singlet Oxygen Sensor Green
(SOSG, Life Technologies). After exposure to a LED light source
(peak emission at 640 nm and energy irradiance of 100 mW/
B
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occur superficially, PDT represents a viable alternative treatment
modality.15
In vitro PDT was performed on human head and neck cancer
cells SQ20B, which are resistant to cisplatin and radiation
therapy. The tumor cell uptake of DBP−UiO was first evaluated
by incubating SQ20B cells with DBP−UiO (30 μg/mL) for 4 or
12 h (Figure S20, SI). The Hf concentrations in the cells were
determined by ICP−MS. No significant difference was observed
between the cells after 4 and 12 h incubations, showing rapid
internalization of DBP−UiO by cancer cells.
To further confirm the PDT efficacy of DBP−UiO, SQ20B
cancer cells were treated with H2DBP, DBP−UiO, or
protoporphyrin IX (PpIX) at various concentrations (5, 10, 20,
50, and 100 μM based on ligand concentrations), and the cells
were irradiated with LED light (640 nm, 100 mW/cm2) for 15
min (total light dose 90 J/cm2) or 30 min (total light dose 180 J/
cm2), respectively. Significant PDT efficacy was observed in
DBP−UiO treated groups, even for the group receiving 5 μM PS
dose and 15 min irradiation (Figure 2d). H2DBP-treated groups
show moderate PDT efficacy only at 20 μM dose with 30 min
light irradiation, while no cytotoxicity was observed in dark
control or blank control groups. In comparison, PpIX is much
less photocytotoxic than DBP−UiO under similar conditions
(Figure 2d).
Figure 2. (a) Absorption spectra of H2DBP and DBP−UiO in PBS. (b)
Singlet oxygen generation by DBP−UiO, H2DBP, and H2DBP + HfCl4.
The dots are experimental data and the solid lines are fitted curves. (c)
Time-resolved fluorescent decay traces of H2DBP and DBP−UiO along
with instrument response function (IRF). (d) In vitro PDT cytotoxicity
of H2DBP, DBP−UiO, and PpIX at different PS concentrations and
irradiation times.
We carried out proof-of-concept in vivo experiments on
SQ20B subcutaneous xenograft murine models to evaluate the
PDT efficacy of DBP−UiO. The mice were treated with PBS
control, DBP−UiO (3.5 mg DBP/kg), or H2DBP (3.5 mg/kg)
by intratumoral injection. Twelve hours post injection, each
mouse was irradiated at the tumor site with light (180 J/cm2) for
30 min. For comparison, photofrin is administrated by
intraperitoneal injection at 10 mg/kg in tumor bearing mice
and with light irradiation of 135 J/cm2.16 As depicted in Figure
3a, the tumors of mice treated with DBP−UiO started shrinking
1 day post DBP−UiO administration and PDT. Most
importantly, among the four tumors in the DBP−UiO group,
two tumors were completely eradicated by single DBP−UiO
administration and single light irradiation, while the sizes of the
cm2; Figure S17, SI), the chemiluminescent reagent SOSG
reacted with O2 to generate green fluorescence, which was
quantified with a fluorimeter. The fluorescence intensity was
plotted against irradiation time (Figure 2b). The 1O2 generation
was depicted with an exponential function that corresponded to a
pseudo first-order process. The 1O2 generation curve was fitted
with the following equation:
1
IF = A(1 − e−kt
)
(1)
where IF is fluorescence intensity and t represents irradiation
time, while A and k are fitting parameters (for detailed
derivations, see SI). The fitted equations for H2DBP and
DBP−UiO are (Table S3, SI)
IH2DBP = 68 × (1 − e−0.0015t
)
(2)
IDBP−UiO = 88 × (1 − e−0.0033t
)
(3)
The product of Ak in the equation is proportional to the initial
1
rate of the reaction that indicates the O2 generation efficiency
(see discussion in SI). DBP−UiO is thus at least twice as efficient
1
as H2DBP in generating O2, presumably owing to heavy Hf4+
1
centers facilitating the intersystem crossing from the DBP to
13
1
3DBP excite state. Consistent with this, the DBP emission
intensity at 640 nm greatly diminished for DBP−UiO (by a
factor of ∼250; Figure S15, SI) with a lifetime reduction from
10.9 ns for H2DBP to 0.26 ns for DBP−UiO (Figures 2c and S16
and Table S2, SI). As a control, addition of Hf4+ to the H2DBP
ligand solution did not enhance but rather reduce the generation
of 1O2 (Figure 2b).
1
Encouraged by the excellent O2 generation efficiency, we
tested the PDT efficacy of DBP−UiO on resistant head and neck
cancer. Head and neck cancer refers to a group of biologically
similar cancers that arise in the head or neck region (including
nasal cavity, sinuses, lips, mouth, salivary glands, throat, and
larynx). Current treatments of head and neck cancers include
surgery and radiation therapy, with chemotherapy and chemo-
radiotherapy playing some roles.14 Since head and neck cancers
Figure 3. In vivo efficacy of PDT on SQ20B tumor bearing mice. (a)
Tumor growth inhibition curve after PDT treatment. Black and red
arrows refer to injection and irradiation time points, respectively. (b)
Tumor weight after PDT treatment. (c) Photos of the mice on Day 8.
(d) Photo of tumors of each group after PDT. Two tumors in the DBP−
UiO group were completely eradicated at the end point.
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Journal of the American Chemical Society
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other two tumors decreased from ∼150 to ∼3 mm3 (Figure 3b−
d). The tumor growth of mice treated with H2DBP was slightly
suppressed after PDT, however, accelerated after 5 days and
exhibited no difference to the control group at the end point.
After local administration, DBP−UiO could be efficiently
internalized by the tumor cells and induce cytotoxicity upon
irradiation, while the free ligand might be cleared away from the
tumor sites before irradiation. No skin/tissue damage was
observed after PDT treatment on all mice (Figure 3c).
Histologies of tumor slices showed macrophage infiltration in
tumors of the DBP−UiO treated group and indicated that
significant fractions of tumor cells were undergoing apoptosis/
necrosis (Figure S21, SI).
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In summary, we have designed and synthesized a stable and
porous DBP−UiO NMOF with an ideal combination of
structural regularity and nanoplate morphology for highly
effective PDT of resistant head and neck cancer. As a result of
site isolation of DBP ligands, enhanced intersystem crossing by
Hf clusters, and facile 1O2 diffusion out of a porous nanoplate, the
NMOF works as an efficient PDT photosensitizer, as
1
demonstrated by both O2 generation efficiency measurements
and in vitro cytotoxicity assays. In vivo PDT efficacy studies with
subcutaneous xenograft murine models demonstrated 50 times
tumor volume reduction in half of the mice and complete tumor
eradication in the other half of the mice that were treated with
DBP−UiO. In comparison, no therapeutic effect was observed in
the mice treated with H2DBP. The facile structural and
compositional tunability of NMOFs should allow further tuning
of other properties to afford a new generation of highly potent
PDT agents for treating resistant cancers in the clinic.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for the synthesis and characterization of
H2DBP, DBP−UiO, and Zn−DPDBP−UiO, photochemical
properties and singlet oxygen generation, cellular uptake, and in
vitro and in vivo efficacy studies. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*wenbinlin@uchicago.edu
■
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Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge NIH (UO1-CA151455) for funding support.
We thank Dr. Cheng Wang, Teng Zhang, Zekai Lin, Christopher
Poon, Carter Abney, and Seth Barrett for experimental help. We
acknowledge the use of the Biophysical Dynamics NanoBiology
Facility, which is partially funded by NIH Grant 1S10RR026988-
01.
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