A mitochondria-targeting supramolecular photosensitizer based on pillar[5]arene for photodynamic therapy

Article abstract of DOI:10.1039/C7CC00950J

A mitochondria-targeting supramolecular photosensitizer system TPP-QAS/WP5/DTAB was constructed based on a host-guest inclusion complex. The supramolecular system could efficiently release and activate TPP-QASs in an acidic environment, which have been demonstrated to preferentially accumulate in mitochondria. Singlet oxygen (¹O₂) could be in situ generated in mitochondria under light irradiation, further enhancing the PDT efficacy.

Full text of DOI:10.1039/C7CC00950J

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
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A mitochondria-targeting supramolecular photosensitizer based
on pillar[5]arene for photodynamic therapy
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
a
a
Leilei Rui , Yudong Xue , Yong Wang , Yun Gao and Weian Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mitochondria-targeting supramolecular photosensitizer system ordered aggregates to achieve controllable delivery of
7
anticancer drugs.
TPP-QASs/WP5/DTAB was constructed based on host-guest
inclusion complex. The supramolecular system could efficiently
release and activate TPP-QASs in an acidic environment, which
Targeted drug delivery systems have received increasing
attention due to their advantages of precise tumor targeting,
enhanced antitumor efficacy and reduced systemic toxicity. In
8
demonstrated to preferentially accumulate in mitochondria. The
1
recent years, precise delivery of therapeutic agents to
subcellular organelles has been exhibited to hold great
promise to further minimize side effects and combat multi-
drug resistance. Mitochondria as vital subcellular organelles in
eukaryotic cells play a critical role in human metabolism, which
singlet oxygen ( O
2
) could be in situ generated in mitochondria
under light irradiation, and then further enhance the PDT efficacy.
Supramolecular chemistry based on modularized and specific
noncovalent interactions have been widely studied with the
aim of developing sophisticated self-assembly systems, such as
molecular machines, supramolecular polymers, and
9
determine the apoptotic cell death. Hence, mitochondria
have been recognized as the subcellular targeting sites for
cancer treatment, since the damage of mitochondria could
induce the mitochondrial dysfunctions and the mitochondria-
1
2
supramolecular gels. Among these noncovalent interactions,
host−guest recogniꢀon has been extensively applied in
1
0
mediated apoptosis. In particular, as mitochondria are
3
supramolecular chemistry. To date, a variety of macrocyclic
hosts have been explored to construct supramolecular
1
1
susceptible to excessive reactive oxygen species (ROS), the
modulation of intrinsic apoptosis by mitochondria-targeting
4
amphiphilies via host−guest recogniꢀon. Pillar[n]arenes, as a antitumor agents associated with the generation of ROS is a
new type of synthetic macrocyclic hosts, also have attracted potential therapeutic approach to eradicate cancer cells.
great interests due to their symmetrical pillar architecture, Recently, Zhang, Wu, Liu, Kim and their co-workers have done
5
12
a lot of works on mitochondria-targeting antitumor agents.
As a noninvasive and reliable cancer-therapy modality with
high spatiotemporal precision, PDT has been received great
facile and high-yield synthesis, and accessible derivatizations.
Nowadays, pillar[n]arene-based host-guest chemistry has been
used in the construction of supramolecular amphiphiles, which
could provide a useful platform for the applications of
supramolecular amphiphiles such as explosive detectors,
1
3
attention.
localizing photosensitizers (PSs) followed by the activation
PDT involves the administration of tumor-
6
with a specific wavelength of light to generate ROS (for
example, singlet oxygen,
transmembrane channels, and drug delivery systems (DDS).
Water-soluble pillar[n]arenes (n = 5, 6) have demonstrated to
be pH-responsive and significantly biocompatible in aqueous
1
2
O ), which ultimately cause
irreversible tissue damage. Unfortunately, most of ROSs have a
short half-life (< 40 ns) and exhibit severely small radius of
2
2
media. Some nascent studies based on host-guest chemistry
of water-soluble pillar[n]arenes have been presented in the
fabrication of stimuli-responsive supramolecular systems.
Recently, Huang, Wang, and Pei have developed a series of
supramolecular amphiphiles based on water-soluble
pillar[n]arenes, which can further assemble to form higher-
1
2a,14
action (< 20 nm).
biomolecules is strongly restricted to the immediate vicinity of
ROS generation.
Thus, the damage of ROS to
1
5
Obviously, transporting the PSs to the
mitochondria for in situ generation of ROS can perturb ROS
homeostasis and further induce cell apoptosis. Additionally,
activatable PSs that can be activated by tumor-associated
stimuli have been developed to further minimize the side
1
5
effect of PDT. Therefore, it is highly desirable to develop pH-
activatable supramolecular photosensitizers nanosystems
based on the host-guest interaction of WP5 and a PS that
possess the ability of mitochondria-targeting, simultaneously,
exhibit enhanced fluorescence and phototoxicity.
Herein, we designed a supramolecular photosensitizer
system using supramolecular amphiphiles based on host-guest
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interaction between WP5 and tetraphenylporphyrin-
containing quaternary ammonium salts TPP-QASs as
photosensitizer to realize PDT (Scheme 1). The supramolecular
(
)
system displayed silenced fluorescence and photoactivity in
physiological environments，whereas in acid conditions, it
could rapidly release the TPP-QASs and efficiently switch to an
active state to dramatically increase the fluorescence signal of
TPP. Interestingly, the released TPP-QASs could selectively
–
5
accumulate in mitochondria because of its lipophilic cationic Fig. 1 (A) Fluorescence spectra of WP5 (2.50 × 10 M, excitation spectrum:
1
290 nm) in aqueous solution at room temperature with different
concentrations of TPP-QASs: 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5, 5.5,
and 6× 10 M in aqueous solution at room temperature. (B) The
fluorescence intensity changes upon addition of TPP-QASs. The red solid
line was obtained WP5 from the non-linear curve-fitting using the above
equation.
2
property. More importantly, the in situ generation of O in
mitochondria further enhanced the PDT efficacy under light
irradiation, leading to substantial cell death due to the
decrease of the mitochondrial membrane potential.
–
5
solution. However, with adding different amounts of WP5 into
TPP-QASs solution, the solution became opalescent, which
means the formation of the supramolecular aggregates.
Moreover, from the fluorescence spectra in Fig. S8, the
emission intensity of TPP sharply decreased with addition of
WP5 content. These phenomena suggested that the host-
guest complexation occurred to form supramolecular
amphiphiles and WP5 has a unique tendency to induce the
aggregation behavior of TPP-QASs by decreasing the CAC (Fig.
Scheme 1. Assembly of TPP-QASs
schematic representation of intracellular tracking and the therapeutic
effect of TPP-QASs WP5 DTAB supramolecular system in cancer cells.
/
WP5
/
DTAB in aqueous media, and
19
S9), enhancing aggregate compactness. Therefore, it was
necessary to determine the molar ratio between WP5 and
TPP-QASs for constructing stable supramolecular aggregates.
The best molar ratio of 10.5:1 (TPP-QASs/WP5) was obtained
for the formation of supramolecular amphiphilic nanoparticles
according to the inflection point based on the results of UV-vis
absorption (Fig. S10). Subsequently, as shown in Fig. S11A, the
ζ potentials of the nanoparticles gradually changed from
positive to negative upon the addition of WP5 in the titration
experiments. In particular, the ζ-potential of the nanoparticles
/
/
1
6
WP5 was synthesized according to established procedures,
and the preparation of TPP-QAS was given in Supporting
Information (Scheme S1 Fig. S1-S4). Since TPP-QAS exhibits
,
poor water solubility, a model guest GM was used to
investigate the host–guest complexations of WP5 and TPP-
1
QAS by H NMR (Fig. S5).It could be seen that the proton
signals of phenyl protons (H
and H ) on WP5 shifted downfield slightly. On the other hand,
1 2 3
) and methylene protons (H , H
constructed at the molar ratio (TPP-QASs/WP5 = 10.5:1) was
close to 0 mV, which means that the nanoparticles obtained at
the molar ratio were not stable, and easily formed the larger
4
the peaks related to protons H
clearly shifted upfield. Whereas, the signals H on GM shifted
a b c d e M
, H , H , H , and H from G
a
6
c
aggregates.
induced increasing stability of nanoparticles, the molar ratio of
:1 TPP-QASs WP5 (ζ potential = −26.80 mV, Fig. S11B) was
Therefore, considering the repulsive-force-
b c d e
upfield slightly and butyl protons (H , H , H , and H ) shifted
upfield remarkably due to the shielding effect of the electron-
rich cavities of WP5. These phenomena suggested that the
complexation between WP5 and GM occurred in aqueous
5
/
chosen for further investigation of its stimuli-responsive
property. Unfortunately, the micellar solution of TPP-
1
7
solution.
QASs
was dialyzed against deionized water for removing DMF. For
solving the problem, DTAB was introduced into the WP5 TPP-
/WP5 (molar ratio, 5/1) generated precipitation when it
The stoichiometry of complexation between WP5 and TPP-
QASs in water was studied by Job’s plot method using the
fluorescence spectroscopy, which demonstrated the 1:1
⊃
6c
QASs amphiphilic system with keeping the molar ratio of 5:1
QASs/WP5 to increase stabilization of the supramolecular
nanoparticles. We speculated that the addition of DTAB into
binding stoichiometry between WP5 and TPP-QASs (Fig. S6).
As shown in Fig. 1A, upon gradual addition of TPP-QASs into
WP5, the fluorescence intensity of WP5 was gradually
quenched, revealing the occurrence of host−guest interacꢀon.
the WP5⊃TPP-QASs amphiphilic system to slightly reduce the
electrostatic repulsion between hydrophilic WP5 and the π-π
stack between TPPs, thus leading to stable nanostructures and
extensive applications.
Reprecipitation technique is often utilized to fabricate stable
supramolecular micelles. Here，TPP-QASs/DTAB (molar ratio,
The association constant (K
0
a
) was determined to be (1.42 ±
.36) × 10 M by using a nonlinear curve-fitting method (Fig.
B), indicating a strong binding affinity between WP5 and
5
−1
1
1
8
QASs moieties. Furthermore, as shown in Fig. S7, a red-shift
was observed from UV−vis absorpꢀon spectroscopy due to
electronic interactions between WP5 and TPP-QASs, further
7/4) DMF solution was added dropwise into WP5 aqueous
6
c, 18
solution with stirring, and then the mixture solution was
dialyzed against deionized water for removing DMF. According
to the best molar ratio, the fluorescence spectra of TPP-
revealing the formation of a stable host-guest complex.
After the establishment of WP5 TPP-QASs recognition
⊃
motif in water, the supramolecular amphiphiles were utilized
to construct stable supramolecular nanoparticles in water.
Firstly, the self-assembly behavior of TPP-QAS itself was
studied. Interestingly, there was no aggregate formed from
TPP-QASs
QASs
measured. As shown in Fig. S12, nearly no fluorescence of the
TPP-QASs WP5 DTAB solution was detected, compared to the
/WP5/DTAB based on supramolecular nanoparticles was
/
/
1
9
strong fluorescence intensity of the TPP-QASs solution. The
2
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indicating TPP-QASs
/
WP5/DTAB supramolecular nanoparticles
had been internalized by the cells. With the increase of
incubation time, red fluorescence intensity increased inside
cells. Upon 24 h of incubation, the strong red fluorescence
could be found in cells, which may suggest the TPP-QASs
molecules had been released from the supramolecular
nanoparticles. More importantly, the fluorescence signals from
Rh123 and TPP-QASs matched well and obvious orange
fluorescence could be found in the mitochondria, revealing the
mitochondria-targeting ability of molecular TPP-QASs upon
1
2b,12e
being released from supramolecular nanoparticles.
Fig.
nanoparticles; (B) TPP-QASs
after the solution of pH was adjusted to 5.0. (C) Size distribution of TPP-
QASs WP5 DTAB supramolecular nanoparticles determined by DLS. Blank
line: pH = 7.4 for 0 h, red line: pH = 7.4 for 12 h, blue line: pH = 5.0 for 12 h.
D) Fluorescence spectra of TPP in TPP-QASs WP5 DTAB supramolecular
micellar solution with the different pH at 25 ˚C after standing for 3h.
2
TEM images: (A) TPP-QASs/WP5/DTAB supramolecular
/
WP5 DTAB supramolecular nanoparticles
/
/
/
(
/
/
-3
CAC of TPP-QASs/WP5/DTAB solution was about 4.7×10 mg
mL measured by the fluorescence absorbance with pyrene as
-1
a probe (Fig. S13). Moreover, the assembled morphology and
size of TPP-QASs/WP5/DTAB aggregates were characterized
by TEM and DLS, respectively. The TEM images exhibited a
spherical nanoparticle with average diameter of around 150
nm (Fig. 2A), which is agreeable with the hydrodynamic
Fig. 3 (A) Confocal laser scanning microscopic images for A549 cells
costained with TPP-QASs/WP5/DTAB nanoparticles and Rh123 at varied
time periods.
diameter (D
h
) of approximately 150 nm calculated by DLS (Fig.
2
C
). Then, the stimuli-responsive behavior of the obtained
The PDT effect can lead to mitochondria damage and the
subsequent apoptosis of cells. For obtaining direct insight into
the toxic mechanism of TPP-QASs/WP5/DTAB supramolecular
nanoparticles, the mitochondrial membrane potential was
monitored using JC-1 dye as the sensor. The results of JC-1
experiments against A549 cells were shown in Fig. 4A. It can
be seen that the clear fluorescence change of JC-1 for the cells
supramolecular nanoparticles was further studied. Compared
to the micellar solution with pH = 7.4, irregular larger
aggregates could be observed in the TEM image (Fig. 2B) after
adjusting pH = 5.0 accompanied by a dramatic increase of
scattering intensity determined by DLS
(Fig. 2C), and
meanwhile the fluorescence intensity at 660 nm
corresponding to the characteristic peak for TPP was
significantly increased (Fig. 2D). All these results suggested the
disassembly of the supramolecular nanoparticles by adjusting
the solution pH to 5.0.
treated
with
TPP-QASs/WP5/DTAB
supramolecular
nanoparticles under different light irradiation time, where the
green fluorescence increased with the increasing irradiation
1
2a,12b,12e
time while the red fluorescence decreased.
The
The pH-responsive TPP-QASs
nanoparticles could be smart for controllable release of TPP-
QASs Fig. S14). The results indicated that a gradual release of
TPP-QASs was determined under acidic conditions (pH = 6.8 or
.0), with the cumulative release amount of 40% at pH = 6.8
and 62% at pH = 5.0 within 12 h, respectively. However, under
the physiological condition (pH = 7.4), the cumulative leakage
of TPP-QASs was less than 20% within 12 h. The results
suggested that the decrease of pH leaded to the destruction of
the supramolecular nanoparticles with concomitant release of
the TPP-QASs molecules.
/WP5/DTAB supramolecular
fluorescent changes of JC-1 revealed that the generation of
ROS could destroy the mitochondria and result in the loss of
the mitochondrial membrane potential. In addition, flow
cytometry also showed a decrease in red fluorescence (FL2
channel) with the increasing time of irradiation after the cells
were treated by supramolecular nanoparticles (Fig. S16),
(
5
further proving the mitochondria damage resulted from the
1
2
O .
To verify the theraputic efficiency of the mitochondrial
targeted supramolecular nanoparticles system, MTT assays
were performed for A549 cell lines after treatment with
different PDT systems. As shown in Fig. 4B, after 24 h
incubation, no obvious cytotoxicity is observed in dark
The cellular uptake of TPP-QASs
nanoparticles was investigated by confocal laser scanning
microscope (CLSM). Firstly, co-localization imaging
/WP5/DTAB supramolecular
-1
condition even at a porphyrin concentration of 10 mg mL
whenever for free porphyrin or TPP-QASs WP5 DTAB
supramolecular nanoparticles. This is because there was no
experiments were performed in A549 cells simultaneously
loaded with molecular TPPs (TPP-QASs or free porphyrin) and
rhodamine 123 (Rh123, a commercial mitochondrial dye) to
demonstrate the subcellular localization of TPP-QASs. As
shown in Fig. S15, the fluorescence of Rh123 and TPP-QASs
overlapped well, and an obvious orange signal was observed in
the merged image, while the nontargeting free porphyrin
exhibited poor colocalization with Rh123. Moreover, Fig. 3
showed the confocal microscopic images for A549 cells
/
/
1
O generated in the dark. Here, only TPP-QASs exhibited a
2
slight dark cytotoxicity for A549 cells compared with the
supramolecular nanoparticles. This may be because positively
charged ammonium ions of TPP-QASs produced the
cytotoxicity, which could be reduced by WP5 coverage in
supramolecular nanoparticles by forming a stable host- guest
1
8
complex. The phototoxicity was further evaluated after the
cells were incubated for 24 h with the different PDT systems
followed by 10 min of light irradiation with visible light LED
costained
with
TPP-QASs
/
WP5/DTAB
supramolecular
nanoparticles and Rh123. It could be found that dotted red
fluorescence in the edge of the A549 cells at 1 h of incubation,
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Fig. 4 (A) Confocal microscopic images for A549 cells incubated with 10 μg
-
mL of TPP-QASs
1
/WP5/DTAB for 24 h at porphyrin concentrations and
then exposed to light emitting diode (LED) lamp light irradiation for 0, 1, 3,
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and 6 min respectively, and then stained with 2.5 μg mL JC-1. “J-aggr” and
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J-mono” are the abbreviations for “aggregation state of JC-1 dye” and
monomer state of JC-1 dye”, respectively. In vitro cytotoxicity of free
porphyrin, TPP-QASs, and TPP-QASs/WP5/DTAB supramolecular micelles
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has low phototoxicity, perhaps due to its low internalization
efficiency (Fig. 4C). The phototoxicity of the supramolecular
nanoparticles increased with the increasing concentration of
porphyrin in the supramolecular nanoparticles, which is much
higher than that of free porphyrin. However, the phototoxicity
of the supramolecular nanoparticles was weaker than that of
TPP-QASs. This is probably because the TPP-QASs contains a
quaternary ammonium cationic ion and the cationic ion has
slight cytotoxicity for cells, further suggesting that WP5 could
decrease the cytotoxicity of TPP-QASs based on host-guest
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As a consequence, the supramolecular
9
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system since its low dark cytotoxicity, high phototoxicity and
selective targeting ability towards mitochondria.
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pH-activatable PSs self-delivery system constructed by host-
guest inclusion complex of TPP-QASs, DTAB, and WP5 in water
for highly efficient of PDT. The supramolecular nanoparticles
system exhibited silent fluorescence and PDT activity at
physiological environment, which subsequently could
efficiently release and activate TPP-QASs in an acidic
environment. More importantly, the released TPP-QASs could
1
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quickly and selectively accumulate in mitochondria in cancer
1
cells. Upon light irradiation, the PS generated O
2
and induced
oxidant damage to the mitochondria, as evidenced by the loss
of the mitochondrial membrane potential, and eventually
leaded to the death of cancer cells.
1
1
This work was financially supported by the National Natural
Science Foundation of China (No. 51173044 and 21574039),
and the State Key Laboratory of Materials-Oriented Chemical
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