Angewandte
Communications
Chemie
Metal–Organic Frameworks
Hot Paper
Controlled Generation of Singlet Oxygen in Living Cells with Tunable
Ratios of the Photochromic Switch in Metal–Organic Frameworks
Abstract: Development of a photosensitizing system that can
reversibly control the generation of singlet oxygen (1O2) is of
great interest for photodynamic therapy (PDT). Recently
several photosensitizer–photochromic-switch dyads were
reported as a potential means of the 1O2 control in PDT.
However, the delivery of such a homogeneous molecular dyad
as designed (e.g., optimal molar ratio) is extremely challenging
in living systems. Herein we show a Zr-MOF nanoplatform,
demonstrating energy transfer-based 1O2 controlled PDT. Our
strategy allows for tuning the ratios between photosensitizer
derivative as a molecular switch to reversibly turn on/off the
1O2 generation was reported.[4] However, the delivery of such
a complex system with multiple components is a formidable
challenge in biological environments owing to the different
molecular properties of each component, resulting in distinc-
tive cell response or permeability.[5]
As a promising class of nanocarriers, metal–organic
frameworks (MOFs) have captured extensive research inter-
est because of their high porosity, synthetic tunability, and
structural diversity.[6] Recently, MOFs have been studied as an
efficient platform for energy transfer between linkers because
of the highly accessible and spatially discrete linkers in the
framework.[7] Herein we show energy-transfer-based 1O2-
controlled PDTusing a Zr-MOFas a nanocarrier, in which the
photosensitizing system installed in the MOF pores can
1
and the switch molecule, enabling maximum control of O2
generation. Meanwhile, the MOF provides proximal placement
of the functional entities for efficient intermolecular energy
transfer. As a result, the MOF nanoparticle formulation
showed enhanced PDT efficacy with superior 1O2 control
compared to that of homogeneous molecular analogues.
1
control the O2 generation using a photochromic switch. A
widely employed photosensitizer, porphyrin[8] and a DTE
derivative were successfully incorporated into the Zr-MOF
with adjustable ratios. Our strategy, therefore, allows opti-
mization of the energy transfer for 1O2 control via fine-tuning
of the ratios between two dyes incorporated into the MOF, as
well as a successful delivery of the dyad into cells.
T
he development of photosensitizers that can control the
generation of singlet oxygen (1O2) has gained increasing
attention in photodynamic therapy (PDT) research to reduce
nonspecific damage from undesirably generated 1O2.[1] PDT is
a minimally invasive cancer treatment using cytotoxic 1O2 that
is generated by energy transfer (EnT) from an excited
photosensitizer to molecular oxygen (3O2) upon appropriate
light irradiation.[2] In this regard, the addition of an activation
step provides another layer of selectivity on top of the
localized nature of PDT, which is based on the directed light
placement at the tumor site. As such, PDTwith an activatable
photosensitizer becomes an appealing therapeutic option
whose sensitizing ability is activated in response to target
stimuli.[1a,3] However, common activation mechanisms often
involve irreversible or passive means. Therefore, the capa-
bility of controlling 1O2 generation in a non-invasive and
reversible manner is highly desired in photosensitizers.
To address this issue, a molecular dyad consisting of
a porphyrinic photosensitizer and a dithienylethene (DTE)
While incorporation of the desired functional molecules
as linkers of the MOF could be straightforward, there are
several major obstacles to be applied in living cells for the
desired 1O2 control. First, porphyrin and DTE derivatives are
not suitable for constructing stable MOFs, compatible in
physiological environments owing to their large sizes.[9]
Moreover, classical mixed-linker strategies to incorporate
multiple functionalities often employ labile coordination
bonds, resulting in an instability of the framework in aqueous
media.[10] In particular, the mixed-linker strategy usually
yields a locked ratio between pre-designed functional mole-
cules in the framework when the linkers are not topologically
identical,[11] which could inherently limit the tuning of the
system for targeted application. Therefore, a system, where
the ratio between photosensitizer and photochromic switch
can be tuned in the MOF, is highly desired to optimize the
[*] J. Park, Dr. D. Feng, Prof. Dr. H.-C. Zhou
Department of Chemistry
1
controllability of O2 generation.
We chose UiO-66 as a base platform to build a photo-
sensitizing MOF system that can realize a reversible control
of 1O2 generation for PDT. As an archetype of Zr-MOF, UiO-
66 exhibits excellent chemical stability through coordination
bonds between high valent ZrIV and carboxylate.[12] Mean-
while, 2,12-connected fcu-a net of UiO-66 allows for many
sub-networks, including bcu-a, reo-a, hxg-a, or high-defect
frameworks.[13] Accompanied with the reduced connectivity,
available coordination sites on Zr6 clusters [Zr6O4OH4-
(COO)12] can be generated for the introduction of the
functionalities via postsynthetic modification.[14] However,
Texas A&M University
College Station, TX 77843 (USA)
E-mail: zhou@chem.tamu.edu
Dr. Q. Jiang
Beijing National Laboratory for Molecular Sciences, Key Laboratory
of Analytical Chemistry for Living Biosystems, Institute of Chemistry,
the Chinese Academy of Sciences
Beijing, 100190 (P.R. China)
Supporting information and the ORCID identification number(s) for
7188
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 7188 –7193