NIR-responsive reversible phase transition of supramolecular hydrogels for tumor treatment

Article abstract of DOI:10.1039/d0tb00935k

Locally administrable drugs with controllable release on external cues hold great promise for antitumor therapy. Here, we report an injectable, supramolecular hydrogel (SHG), where the drug release can be controllably driven by near infrared (NIR) irradia

Full text of DOI:10.1039/d0tb00935k

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Pages 341-528
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ISSN 2050-750X
PAPER
Wei Wei, Guanghui Ma et al.
Macrophage responses to the physical burden of cell-sized
particles
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DOI: 10.1039/D0TB00935K
ARTICLE
NIR-Responsive Reversible Phase Transition of Supramolecular
Hydrogels for Tumor Treatment
Ting Zhang,a Zhiyu Liu,c Hüsnü Aslan,d Chunhua Zhang*a and Miao Yu*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Locally administrable drugs with controllable release on external cue holds great promise for antitumor therapy. Here, we
report an injectable, supramolecular hydrogel (SHG), where the drug release can be controllably driven by near infrared
(NIR) irradiation. The SHGs are formed by electrostatic interaction with laponite (XLG), in which upconverting nanoparticles
(UCNPs) modified with α-cyclodextrin (α-CD) are used as the core, and azobenzene quaternary ammonium salt (E-azo) are
further assembled through host-guest interaction. The hydrogel demonstrates reversible phase transition between gel and
sol state and photothermal conversion capability. In detailed in vitro and vivo trials, drug-loaded SHGs successfully
suppressed invasion by cancer cells. Such phase transition by remote NIR-switch hence the photothermal effect-promoted
drug release emphasizes the considerable potential of supramolecular hydrogel in anticancer therapies, espeically for the
treatments requiring long-term, on-demand drug supply in clinic.
irreparable, SHGs could be customized in biomedical
applications to match the mechanical properties and properties
of target biological tissues, such as on-demand reversible gel
Introduction
Designing
and
synthesizing
nano-assemblies
by
behavior, self-healing ability, thixotropy and stimulation
reactivity.6 As drug carriers, SHGs present good biocompatibility
and degradability, efficient drug loading and appropriate
protection on labile drugs from degradation, together with
spatial/temporal control of the drug release.7 To avoid invasive
implantation and risks associated with surgery, injectable SHGs,
especially their on-demand drug release at the tumor site
driven by external light, have sparked considerable interest.8
However, most of the developed SHGs drug carriers were
ultraviolet (UV)/visible light-responsive, which are undesirable
due to the limited penetration and irradiation damage.9 In this
regard, near infrared (NIR) light-activated drug release of SHGs
is highly preferred.10
Herein, we report an injectable SHG as a high-load drug
carrier, where the drug release is driven by NIR irradiation. As
illustrated in Scheme 1, upconverting nanoparticles (UCNPs),
i.e. NaYF4:Yb3+,Tm3+@NaYF4, are fabricated as the core and
covalently coated by α-cyclodextrin (α-CD), which are further
assembled with azobenzene quaternary ammonium salt (E-
azo) through host-guest interaction. The resultant UCNP@α-
CD-E-azo forms a stable, injectable SHG with laponite (XLG) clay
via electrostatic interaction, showing high biocompatibility and
stability. Upon NIR irradiation, the UCNPs convert the absorbed
NIR light into UV emission and heat, inducing E-to-Z
isomerization of azo hence a gel-to-sol phase transition, which
is promoted by the photothermal effect. The phase transition
then enables the drug release efficiently. As the phase
transition is reversible, the drug release can be turned in a
controlled manner by switching the irradiation. Such a high-
supramolecular chemistry for tumor therapy have become a
fascinating strategy.1 Besides the distinct merits, such as
predictability, reversibility, and adjustability, supramolecular
assemblies (e.g. micelles, vesicles, hydrogels, etc.) have
sensitive response to various triggers.2 Small shifts in
environmental pH, temperature, light, ionic strength or solvent
polarity are often adequate to induce dramatic changes of their
assembly form,3 showing promising potential for controlled
delivery of drugs and genes.4
Supramolecular hydrogels (SHGs), which are combined by
reversible non covalent interactions among their constituent
molecules including hydrogen bonding, electrostatic
interaction, metal ligand coordination and hydrophobic
association, have attracted much interest as biomaterials,
binder, sewage treatment and 4D printing.5 Compared to fully
covalent crosslinked hydrogels, they are opaque, fragile and
a. T. Zhang, Prof. C. H. Zhang, MIIT Key Laboratory of Critical Materials Technology
for New Energy Conversion and Storage, School of Chemistry and Chemical
Engineering, Harbin Institute of Technology, P. O. Box 1254, Harbin, 150001, P. R.
China. Email: zhangchunhua@hit.edu.cn
b. Prof. M. Yu, School of Chemistry and Chemical Engineering, Harbin Institute of
Technology, Harbin, 150001, P. R. China. Email: miaoyu_che@hit.edu.cn
c. Z. Liu, Department of Chemistry and Biochemistry, University of California, Los
Angeles, Los Angeles, California 90095
d. Dr. A. Hüsnü, Interdisciplinary Nanoscience Center (iNANO), Aarhus University,
The iNANO House, Gustav Wieds Vej 14, 8000 Aarhus C
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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load, biocompatible drug carrier with switchable, controllable EtOH. The mixture solution were stirred overnight with vigorous
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drug release upon NIR holds great promise for antitumor magneticly at room temperature, at DwOhI:i1c0h.10p39o/iDn0tTBi0t09w35aKs
treatments in clinic.
transferred to a centrifuge tube and then hexanes were added.
The UCNP-Gly were collected by centrifugation at 8000 rpm for
15 min and dried in a vacuum.
Synthesis of UCNP@α-CD. α-CD-NH-NH2 was prepared
according to previous reference.11 The precipitated 50 mg
UCNP-Gly nanoparticles were redispersed in anhydrous DMF
(3.0 mL). And α-CD-NH-NH2 (300 mg), N, N-
diisopropylethylamine
(82.5
mg),
1H-benzotriazol-1-
yloxytripyrrolidinophosphonium hexafluorophosphate (132.8
mg) were added into the solution. The solution was intensely
stirred two days under N2 atmosphere and centrifuged. The as-
prepared nanoparticles were dispersed in distilled water, and
excess ligands and catalysts were removed through dialysis.
Synthesis
of
compound
(E)-N,N,N-trimethyl-1-(4-
(phenyldiazenyl)phenyl)methanaminium (E-azo). Firstly, the
mixture of 2.70 g p-aminotoluene, 2.70 g nitrosobenzene and
30.0 mL acetic acid were added to a round bottom flask and
stirred for 24 h vigorously under N2 atmosphere. The precipitate
were separated by column chromatography to afford a red solid
compound 1 (55%). Then, 1.0 g as-prepared compound 1, 1.1 g
N-bromosuccinimide (NBS) and 65.0 mg α-azoisobutyronitrile
(AIBN) were added to 20.0 mL CCl4 and refluxed for 24 h. The
product were collected through vacuum distillation and
purificated by column chromatography on silica gel to get the
red solid compound 2 (82.0%). When E-azo was synthesized, a
solution of 2.70 g compound 2 in 25.0 mL ethanol and 25.0 mL
trimethylamine (30.0% in ethanol) were reacted at 80 °C for 24
h. The solution was concentrated by decompression, further
dissolved in water and washed several times with
dichloromethane. The crude product was further crystallized
and purified by methanol, and dried in vacuum at 50℃ to obtain
Scheme 1 Schematic illustration of the assembly and NIR-
triggered phase transition of the injectable SHGs.
Experimental section
Characterization. 1H NMR, 13C NMR spectra and NOESY
spectrum were measured by a Bruker AVANCE AV400. ESI-MS
were recorded on a Agilent 6520 Q-TOF-MS. TEM images and
SEM images were examined by a Philips EM400st transmission
electron microscope and a JEOL JSM-7500F scanning electronic
microscope, respectively. UV/vis spectra were recorded on a
Shimadzu UV-3600 spectrophotometer equipped with a PTC-
348 WI temperature controller. X-ray diffraction (XRD) was
conducted using a Siemens D5005 diffractometer with Cu Kα
radiation at 40 kV and 30 mA. Zeta potential and the dynamic
light scattering (DLS) were measured by Brookhaven
Instruments at 25 °C. Rheological tests of hydrogels were
carried out by using an Anton Paar model MCR-301 rheometer,
with a 25 mm diameter parallel plate attached to a transducer.
Thermal gravimetric analysis (TGA) were measured by using a
NETZSCH TG209 under N2 atmosphere. The fluorescence
spectra were surveyed by HORIBA FL-3. NIR laser light (980 nm)
source come from Hi-tech optoelectronics Co.,Ltd.
1
the pure orange-yellow solid (50.0%). H NMR (400 MHz, D2O)
δppm = 7.85 (d, 2H), 7.80 (d, 2H), 7.66 (d, 2H), 7.54 (m, 3H), 4.48
(s, 2H), 3.05 (d, 9H). 13C NMR (400 MHz, D2O) δppm =153.33,
152.03, 133.99, 132.26, 130.16, 122.74, 68.84, 52.45. HRMS [M-
+
Br]- calcd for C16H20N3 : 254.1652. Found: 254.1655.
Synthesis of supramolecular hydrogels (SHGs). 100.0 mg
Laponite (XLG) were suspensed in 4.0 mL deionized water with
vigorously stirring for 15 min at 25 °C. Then, 3.0 mg, 0.5 mL
sodium polyacrylate was added into the solution and reacting
for 20 min. Nextly, a solution of UCNP@α-CD-E-azo (38.5 mg,
0.5 mL) was added and kept stirring for 3 min. After the
reaction, the SHGs remained upright and stationary for 1 h.
Drug loading and releasing in vitro. In the process of DOX-
loaded supramolecular hydrogel synthesis, 100.0 mg XLG were
suspensed in 4.0 mL deionized water with vigorously stirring for
15 min at 25 °C. Then, 3.0 mg, 0.5 mL sodium polyacrylate was
added into the solution and reacting for 20 min. Nextly, a
solution of UCNP@α-CD-E-azo (38.5 mg, 0.5 mL) and 5 mg DOX
were simultaneously added and mixed to prepare DOX-
UCNP@α-CD-E-azo/XLG. The calculation formula of DOX
encapsulation rate was as follows:
Materials. Unless otherwise specified, all solvents and reagents
could be used directly without further treatment. Rare earth
compounds (YCl3·6H2O, YbCl3·6H2O, TmCl3·6H2O), N, N-
diisopropylethylamine,
oleic
acid,
1H-benzotriazol-1-
yloxytripyrrolidinophosphonium hexafluorophosphate are all
obtained from Aladdin. And 1-octadecene, 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),
propidiumiodide (PI) and 4,6-diamidino-2-phenylindole (DAPI)
are purchased from Sigma-Aldrich. Glyphosine (Gly) is
purchased from Macklin. Laponite (XLG) is bought from
Rockwood Additives Ltd.
Synthesis of UCNP-Gly. Approximately 150 mg of precipitated
UCNPs were added to a 50.0 mL flask along with 8.0 mL CHCl3
and absolute 2.0 mL EtOH. Then, 600.0 mg glyphosine (Gly)
were added to the mixture of 2.0 mL CHCl3 and absolute 2.0 mL
DOX encapsulation rate (%) = (mL/m0) × 100 %
where mL and m0 are mass of DOX loaded in the UCNP@α-CD-
E-azo/XLG supramolecular hydrogel and mass of DOX added,
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respectively. The mass of DOX was determined at 480 nm by a azo/XLG with NIR light irradiation), group 5 (DOX-UCNP@α-CD-
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DOI: 10.1039/D0TB00935K
UV spectrophotometer. 5.0 mg DOX-UCNP@α-CD-E-azo/XLG E-azo/XLG), and group 6 (DOX-UCNP@α-CD-E-azo/XLG with NIR
supramolecular hydrogel were fully dissolved in 15.0 mL PBS of light irradiation). Mice in the group were injected with 100 µL
different pH values under conditions of darkness or 980 nm (1 PBS or 100 µL, 1 mg mL-1 UCNP@α-CD-E-azo/XLG (UCNP@α-CD-
W cm‒2, 2 W cm‒2, 3 W cm‒2) laser illuminate for different time. E-azo:XLG=38.5:100 wt%) and DOX-UCNP@α-CD-E-azo/XLG
At different points in time, the samples were centrifuged, and (UCNP@α-CD-E-azo:XLG:DOX=38.5:100:5 wt%) intratumorally,
the supernatant was examined by UV-Vis spectroscopy to respectively. After 2 h postinjection, the mice were exposured
determine the dose released.
by NIR light (980 nm, 1.0 W cm−2) for 30 min. After six groups of
In vitro cell cytotoxicity assay. The MTT assay on HepG2 treatment, tumor volumes and weights of all mice were
(hepatoma cell line) cells and L02 (normal human liver cells) monitored daily and then normalized with the original values.
cells were used to analyze the cell viability in vitro. HepG2 cells The calculation equations of tumor volume (Tvolume) was as
and L02 cells were seeded into 96-well plates for 24 h with a follows:
density of 1.0 × 104 per well in 100 µL DMEM medium,
Tvolume = (Tlength) × (Twidth)2/2
respectively. Then, different concentrations of UCNP@α-CD-E- where Tlength and Twidth are length and width of tumor measured
azo/XLG and DOX-UCNP@α-CD-E-azo/XLG were added and with a caliper, respectively. Relative Tvolume was calculated for
continued to incubate for 24 h. Nextly, 20.0 µL, 5.0 mg mL−1 MTT V/Vi, and relative Tweight were calculated for W/Wi. Vi and Wi are
solution was added into per well and incubated for another 4 h. original values of mice.
After that, the media was removed and 150.0 µL DMSO was Histology analysis. After treatment, the tumor sections and
added for 0.5 h then replaced and wanshed. Finally, the important organs (heart, spleen, liver, kidney and lung) of mice
absorbance was monitored at 490 nm by a microplate reader were collected, and fixed with 4% paraformaldehyde and
(SynergyTM HT).
embedded in paraffin. Staining with H&E was applied to the
Fluorescence imaging. For observing cellular uptaking and DOX main organs and tumor sections of mice for histological
releasing, HepG2 cells were incubated in a 6-well plates for 24 analysis. At last, Olympus BX53 fluorescence microscope was
h. Then, UCNP@α-CD-E-azo/XLG and DOX-UCNP@α-CD-E- applied to obtain the optical microscope images.
azo/XLG were added into the above medium for 6 h at a dose of Haematological analysis. Collecting 20 µL blood of all mice after
250.0 µg mL−1. Then washing medium three times with PBS, the treatment at 14th day and using a HF-3800 blood analyzer for
cleaned medium were added into the culture plate. And the haematological analysis.
medium were exposed with NIR light (980 nm, 1.0 W cm−2) for
30 min. After incubation, PI was added and stained for 30 min,
then washed with PBS for several times. Similarly, in the cell
RESULTS AND DISCUSSION
uptake experiment, DAPI was added to the culture medium and
dyed for 30 min. Finally, the medium were washed with PBS for
three times and exposed with NIR light (980 nm, 1.0 W cm−2) for
30 min. The fluorescence images were observed in a Leica
DFC450 C Microsystems.
Confocal laser scanning microscopy (CLSM). Firstly, 5.0 × 104
HepG2 cells were cultured in 0.5 mL DMEM for 24 h in
coverglass bottom dishes of 6-well plates at 37 °C. After
incubating with DOX-UCNP@α-CD-E-azo/XLG for 6 h, the
culture medium was discarded. Then, the medium washed with
PBS three times and exposed with NIR light (980 nm, 1.0 W
cm−2) for different time. Nextly, DAPI was added into the
medium and followed by incubation for 15 min. The medium
was washed with PBS for several times, and 1 mL PBS solution
were added. The CLSM images were acquired using Confocal
Software (FluoView FV1000, Olympus).
In vivo antitumor effect. For animal experiments, female Balb/c
nude mice which about four or five weeks old were bought from
Vital River Laboratory Animal Technology Co., Ltd. And all
animal were implemented in accordance with the standard of
the National Regulation of China for Care and Use of Laboratory
Animals. Then, HepG2 cells were distributed in DMEM to build
tumor models, and followed by injecting Matrigel in the left
front leg of all mice. Untill tumor volume grew to150 mm3, all
mice were divided in six groups randomly, five mice in each
group. Group 1 (PBS solution), group 2 (NIR light irradiation),
group 3 (UCNP@α-CD-E-azo/XLG), group 4 (UCNP@α-CD-E-
Construction of NIR-responsive supramolecular hydrogels
(SHGs). The synthesis and characterization of compound E-azo
are presented in the Schemes S1 and Fig. S1–S3.12 The oleic acid
(OA)-capped UCNPs were produced according to the method
reported previously.13 Their transmission electron microscope
(TEM) images showed monodisperse, uniform particles with an
average size of 30 nm (Fig. S4a and S4b). High-resolution TEM
(HRTEM) images was shown in Fig. S4a inset, and X-ray
diffraction pattern was displayed in Fig. S5, they revealed that
the nanoparticles possess high crystallinity, where the d100
=
0.51 nm is well indexed to hexagonal NaYF4. Next, OA on UCNPs
was substituted by glyphosine ligands.14 The carboxylic group of
the glyphosine ligands facilitated conjugation with
ethanediamine-functionalized α-CD through a condensation
reaction. The representative TEM, HRTEM, scanning electron
microscope (SEM) images and XRD pattern of the obtained
UCNP@α-CD (Fig. S4c, S4d and S5) indicated that the particles
maintained similar size, morphology, and crystallinity like the
UCNPs.
The covalent bonding of α-CDs on UCNPs was proved by the
characterization of Fourier-transform infrared spectroscopy
(FTIR). As shown in Fig. S6, compared with the strong bands at
2920 and 2850 cm−1 ascribed to the stretching vibration of CH2
groups for UCNPs, additional bands at 1156 and 925 cm–1
(corresponding to the stretching vibration of P=O groups and P–
OH groups, respectively), 1420 cm–1 (attributed to the typical
symmetric stretching vibration of carboxyl), 3300 cm–1 (dued to
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the stretching vibration of NH2), 754 and 701 cm–1 (ascribed to azo and XLG solution formed transparent, typical hydrogel,
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the bending vibration of NH), and 1638 cm–1 (associated with which was readily transformed into free-DstOaIn: 1d0i.n10g3p9/rDo0dTuBc0t0(9F3i5gK.
the stretching vibrations of amide), appeared in the spectrum 1b). The gel presented three-dimensional scaffolding
of UCNPs@α-CD, suggesting the presence of ethylenediamine- frameworks constructed by thin flakes, integrating the polymer
modified α-CD. Moreover, the evident change from being with the dark particles (Fig. 1c and 1d).
hydrophobic to hydrophilic (photos in Fig. S7) and the varied
Remarkably, upon a short 980 nm light illumination (1 W
zeta potential (Fig. S8) from +17.69  0.92 mV to ‒6.50  0.34 cm‒2, 30 min), pronounced gel-to-sol phase transition occurred
mV also supported a successful surface modification by α-CD. (Fig. 1e), allowing the product to be injected through a narrow
Thermogravimetric analysis (TGA) showed that the α-CD-NH- syringe needle (Fig. 1f). Remarkably, the phase transition was
NH2 content in UCNP@α-CD was ~11.1% (Fig. S9).15
reversible, i.e. upon exposed by 420 nm visible-light (1 W cm‒2)
Photoluminescence (PL) spectra of UCNPs and UCNP@α-CD for 10 min, the sol was changed back to gel. Such gel-to-sol and
were collected with the excitation wavelength of 980 nm (Fig. sol-to-gel phase transition can be repeatedly triggered by
S10), showing three emission peaks at ~360, 452 and 474 nm, applying NIR and visible light alternatively.
which corresponded to the D2→3H6, D2 →3F4, and G4→3H6
transition from Tm3+, repectively. And decreased emission
intensity of UCNP@α-CD relative to that of UCNPs may be
mainly dued to the light-scattering effect caused by
modification of α-CD. Directly illustrated by the inset photo in
Fig. S10, the significant PL emission also suggests the potential
for imaging and sensing of the product.16
1
1
1
e
f
a
b
To further modify the particles using host-guest chemistry,
we first investigated the interaction between α-CD and E-azo by
1H nuclear magnetic resonance (NMR) titration method,
indicating that these two components followed α-CD:E-azo=1:1
binding (Fig. S11). Following a nonlinear least squares curve-
fitting method, the corresponding KS value was calculated to be
4.89 × 105 M−1, based on the sequential changes in chemical
shifts (δ) of Hd at gradually increased concentrations of α-CD.17
c
d
Mixing α-CD with E-azo solution resulted in the signals of the Fig. 1 Digital photos of (a) individual XLGs and (b) UCNP@α-CD-
azo groups had a significant downfield shift, and at the same E-azo/XLG SHG, (c) TEM and (d) SEM images of UCNP@α-CD-E-
time the proton signals for Hc and Hd, i.e (adjacent protons of azo/XLG SHG, (e) Photo of UCNP@α-CD-E-azo/XLG SHG under
diazo group on the two benzene rings) got broadened (Fig. S12b 980 nm irradiation (1 W cm‒2), (f) Demonstration of SHG
and S12c). The cross-peaks of the proton signals between the injecting.
azo groups and α-CD in the NOESY spectrum (1:1 equimolar
mixture of α-CD-E-azo) was shown in Fig. S13a, further
The phase transitionoriginates from the isomerism of E-azo.
confirmed that E-azo unit as a guest integrated into the cavity As shown in the ultraviolet-visible light (UV‒vis) absorption
of a-CD molecule. In addition, a decrease in relative intensity spectra (Fig. S15), the absorbance of E-azo alone (0.05 mM) at
and a small hypsochromic shift of the main absorption band of 318 nm dropped to the lowest value upon UV irradiation (365
the E-azo chromophore (at 319 nm corresponding to π–π* nm, 10 min), and restored upon visible light irradiation (420 nm,
transition) were detected from the mixture (Fig. S14). 40 s). The isomerization ratio of E-azo was estimated to be
Meanwhile, the n–π* transition also caused the descent and 67.87%. Consistently, the absorbance variation was reversible
widening of the absorption peak at 428nm. Above changes can upon multiple repeated cycles of UV and visible light irradiation.
be attributed to the intermolecular interactions and polarity Similar photo-induced isomerization also occurred in α-CD-E-
changes of the chromophore, indicating the formation of α-CD- azo, upon even shorter irradiation. UV irradiation as short as 3
E-azo complex, in consistent with the literature.18 The zeta minutes can already reduce the absorbance to the lowest value,
potential of UCNP@α-CD-E-azo further increased to 15.88  and another visible light irradiation for just 20 s can restore the
0.48 mV, due to the participation of positively-charged azo absorbance to the maximum (Fig. S16). The results suggest that
group (Fig. S8).
the isomerization rate of E-azo can be improved by their
The SHG was fabricated via a hierarchical self-assembly integrating with macromolecular α-CD. The reversible photo-
strategy. Sodium polyacrylate modified XLGs were used to isomerization of α-CD-E-azo showed no obvious decay after
improve the electronegativity of the XLGs surface and enhanced multiple UV-visible light irradiation cycles.
the mechanical property of hydrogels by electrostatic
In good accordance, after UV irradiation for 10 min, signals
interaction.19 A decrease in zeta potential from -14.32  0.85 corresponding to the Hc*',d*' protons in the H NMR of α-CD-E-
mV (pure XLG) to -29.41  1.1 mV (XLG-Sodium polyacrylate) azo also showed significant up-field shift relative to Hc',d' protons
demonstrated a successful modification of sodium polyacrylate before irradiation (Fig. S12c‒d). In comparison, the spectrum of
(Fig. S8). Distinct from the aqueous solution of XLG alone (2 Z-azo alone was barely varied under the same irradiation
wt%) showing no gelation (Fig. 1a), mixture of UCNP@α-CD-E- conditions (Fig. S12a). All these results suggested that the UV-
1
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irradiation-induced E-to-Z isomerization of azo units can release rate further increased (Fig. 2c). We also evaluatedVtiehweArrteiccleoOvnelirnye
DOI: 10.1039/D0TB00935K
the azo units from the a-CD cavity. The point was further performance of the gel by alternatively applying 100% and 0.1%
confirmed by the vanished correlation peaks in the NOESY strain amplitude, when the fixed frequency was 1.0 Hz. From
spectrum (Fig. S13b).
Fig. 2d, SHGs exhibited liquid and solid state alternatively,
Similar E-to-Z isomerization occurred for the UCNP@α-CD-E- showing swift response and reliable recovery. Besides, the
azo upon NIR irradiation with the isomerization rate in an rheological testing of the supramolecular hydrogels after
irradiation power-dependent manner (Fig. S17), whilst no alternating irradiation with NIR and visible light (Fig. 2b red
optical absorption variation were observed for α-CD-E-azo triangle), showed no obvious mechanical strength loss as
under the same conditions (Fig. S18). The results indicate that compared to the original hydrogel, thus indicating the complete
NIR-to-UV light conversion mediated by UCNPs can also induce recovery of the supramolecular hydrogel after the reversible
the E-to-Z transformation of azo effectively in UCNP@α-CD-E- light induced phase-transition process.
azo and lead to the gel-to-sol transition.
Drug Loading and Release Behaviors of the DOX-SHGs. To
Mechanical properties of the SHGs. We then investigated demonstrate drug loaded and delivery behaviors, doxorubicin
mechanical properties of the SHGs by rheological experiments. (DOX), a typical chemotherapeutic drug, was selected as an
When angular frequency of applied external strain was 0.1 rad example. DOX was mixed with UCNP@α-CD-E-azo and XLG to
s‒1, the storage moduli (G') and loss moduli (G") were plotted as form the drug-loaded hydrogel, i.e. DOX/UCNP@α-CD-E-
functions (Fig. 2a). And G' and G" maintained practically azo/XLG. The absorption peak at about 480 nm demonstrated
constant and G' larger than that of G" at a strain from 0.1% to that the drug DOX were successfully loaded into the hydrogel
10%. It demonstated that SHGs were steady and involved (Fig. S19). The drug encapsulation rate was calculated as 95%.
physical crosslinking were not compromised. When the strain is The drug release was first evaluated in the dark at 37 °C (Fig.
further increased, G' dropped faster than G" did. Under a strain 3a): the release was pH sensitive and favored an acidic
of 50%, G' became smaller than G", indicating the occurrence of environment (34.6±1.1% at pH 5.0 vs. 1.6±0.8% at pH 7.4). Then
gel-to-sol transition.
we monitored DOX releasing at pH 5.0 in the dark for 60 min
followed by NIR irradiation (Fig. 3b), showing that the NIR light
can evidently boost the release even at low pH. The DOX release
followed an irradiation-duration dependent fashion (Fig. 3c):
under 980 nm irradiation (1 W cm‒2), it took 30 min to release
38.9±2.0% and 4 h to release 61.7±1.9%. The influence of
irradiation intensity was also explored: upon 4h irradiation, the
total release was enhanced from 61.7±1.9% to 88.7±2.1% when
the applied irradiation density increased from 1 W cm‒2 to 3 W
cm‒2. Moreover, a distinct “on-off” pattern of the release was
observed when the NIR light was switched on then off in the
dark at pH 5.0 (Fig. S20), suggesting the possibility of remotely
controlling the release process and release dose by varying NIR
intensity.
a
b
c
d
Photothermal effect of the SHGs. In addition, the UCNPs have
a good photothermal effect,20 thus we investigated the effect of
temperature on the SHGs. Upon NIR light irradiation, the
Fig. 2 (a) Dynamic strain scanning curves of the SHG when the temperatures of UCNP@α-CD and UCNP@α-CD-E-azo/XLG
angular frequency was 0.1 rad s‒1, (b) dynamic frequency increased linearly when increasing power density in a range of
scanning curves of the SHG (black squares) and after irradiation 0‒3.0 W cm-2, while the pure XLG had little change (Fig. 3d). The
alternatively with NIR and visible light (red triangle) when the excellent photothermal properties of the SHGs were proved,
strain was of 1.0%, (c) the shear stress and viscosity of the SHG the temperature increased about 8.0 °C with 980 nm light
as the function of shear rate, and (d) the variations in strain irradiation. Then, the effect of temperature on the hydrogel
amplitude of 100% and 0.1% alternatively for the SHG.
phase transition was studied. When heated to 45.0 °C
externally, pure XLG had a phase transition, but DOX-loaed
After analyzing the viscoelastic region, we chose strain of 1% SHGs still remain hydrogel state (Fig. S21). The drug release
to investigate the sensitivity of the gel to the oscillation behavior of pure XLG and DOX-UCNP@α-CD-E-azo/XLG were
frequency. As shown in Fig. 2b (black squares), G' was larger presented in Fig. S22 and Fig. 3a. DOX release in DOX-UCNP@α-
than G", and both did not show any obvious change at an CD-E-azo/XLG did not change significantly at 37.0 °C and 45.0
angular frequency from 0.1 to 100 rad s‒1, indicating gelation of °C. These results suggested that NIR irradiation of the SHGs can
product. Moreover, when the shear rate was 0.015 s‒1 was produce photothermal effects, but the resulting heat cannot
applied, the viscosity of the SHGs reached the maximum, and cause a phase transition. The phase transition occured only in
produced the phenomenon of apparent decline as the shear the condition of NIR irradiation.
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DOI: 10.1039/D0TB00935K
a
b
c
d
Fig. 3 DOX release from the DOX-UCNP@α-CD-E-azo/XLG
hydrogel (a) in pH 7.4 and pH 5.0 at different temperature under
the dark, respectively, (b) at pH 5.0 when keeping in the dark
for first 60 min and irradiated by NIR light afterwards (Inset:
photographs of the SHG, showing the obvious change of the red
zone before and after drug release), (c) at pH 5.0 upon NIR
irradiation of various power density. The NIR irradiation is 980
nm (1 W cm‒2). (d) The temperature changes of pure XLG,
UCNP@α-CD, UCNP@α-CD-E-azo/XLG in aqueous dispersion
under NIR light irradiation at various power densities. Samples
were dispersed in aqueous solution at the same concentration.
Fig. 4 Bright optical images and fluorescence images of HepG2
cells treated without (Control), with DOX-UCNP@α-CD-E-
azo/XLG (250 μg mL‒1) for 1 and 3h in the dark (1h and 3h), and
with DOX-UCNP@α-CD-E-azo/XLG (250 μg mL‒1) with 980 nm
light irradiation for 30 min at 1 W cm‒2 (3h + NIR). The cells were
stained with DAPI after various treatments. Based on the
merged images of DAPI (blue) and DOX signal (red), the
distribution of DOX in the cell can be revealed. The NIR
irradiation is 980 nm (1 W cm‒2) for 30 min, Scale bar = 50 µm.
Since the UCNPs and the polymer in the UCNP@α-CD-E-
azo/XLG are known for high biocompatibility, the results thus
imply that the gel-to-sol phase transition UCNP@α-CD-E-
azo/XLG upon NIR irradiation has certain effect on cancer cell
inhibition. Reasonably, the inhibition effect was largely
improved with the released drug: for HepG2 cells incubated
with DOX-UCNP@α-CD-E-azo/XLG at the same concentration,
the cell viability decreased to 31.4±3.5 %, due to the efficient
drug release upon the NIR irradiation (Fig. S23b). Notably, after
the same combined treatment, the survival rate of normal cells
L02 (58.5±2.66 %) are higher than that of cancer cells (Fig.
S24b). It revealed the toxicity specificity of the SHGs on cancer
cells. That is because the acidic environment around cancer cells
promotes drug release, in consistent with previous literatures.21
To intuitively demonstrate the cancer cell inhibition effect of
the SHG in vitro, the DOX-UCNP@α-CD-E-azo/XLG (250 μg mL‒1)
treated HepG2 cells were stained with propidium iodide (PI),
and red fluorescent signals were used to distinguish dead cells.
In Vitro Cell Cytotoxicity and NIR-Responsive Treatment. To
explore the celluar uptake performance of the SHGs, HepG2
cells were incubated with DOX-UCNP@α-CD-E-azo/XLG for 1.0
and 3.0 h in the dark as well as 3.0 h under NIR irradiation,
respectively, then stained with 4',6-diamidino-2-phenylindole
(DAPI). From Fig. 4, different from the control group where no
red signal was observed, red fluorescence corresponding to
DOX was presented in the cells after 1 h incubation with the SHG
in the dark, implying the effective cellular uptake of the SHG.
The red signal was enhanced when the incubating period was
extended from 1.0 h to 3.0 h. Importantly, by combination of
the SHG with NIR irradiation, the red fluoresence was largely
boosted, and the signal distribution varied from cytoplasm to
nuclei as well. The results indicate that NIR irradiation can not
only enhance the celluar uptake of the SHG, but also trigger the
drug release.
The therapeutic performance of the SHGs was first examined
in vitro on HepG2 (a cancer cell line) and L02 cells (a normal cell
line) by MTT assay. When incubating with UCNP@α-CD-E-
azo/XLG and DOX-UCNP@α-CD-E-azo/XLG at a concentration
up to 1000 μg mL‒1 in the dark for 24 h, respectively, the cell
viability of both cells was barely reduced (Fig. S23a and S24a),
indicating the stability and low cytotoxicity of the SHG if any.
Interestingly, upon NIR illumination (980 nm, 1 W cm‒2, 30 min),
UCNP@α-CD-E-azo/XLG (250 μg mL‒1) without loading the drug
can already induce cell death of 24.7% to the treated HepG2
(Fig. S23b). The photothermal effect of UCNPs causes a rise in
temperature, which could kill some cancer cells.
a
b
Fig. 5 CLSM images of DOX-UCNP@α-CD-E-azo/XLG hydrogel in
HepG2 cells before (a) and after (b) NIR light irradiation for 30
min (980 nm, 1 W cm-2). Scale bar = 25 µm.
6 | J. Name., 2012, 00, 1-3
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As shown in Fig. S25b-j, the cells in the control group (Fig. S26b). Moreover, the tumor tissue sections with
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presented no significant red signal, revealing the low toxicity of hematoxylin and eosin (H&E) staining (FDigO.I:S1206.1c0)3r9e/Dv0eTaBle0d09t3h5eK
the SHG. In consistent with the results of MTT assay, applying most severe tissue damage from Group 6. All these results
combination of 250 μg mL‒1 DOX-loaded SHGs with NIR light emphasize the high antitumor competency of the drug-loaded
(980 nm, 1 W cm‒2) illuminate for 30 min which killed the cancer SHG under NIR irradiation, which are attributed to the NIR-
cells effectively, illustrated by the apparently increased red driven gel-to-sol phase transition hence the efficient drug
signal in the fluorescence image (Fig. S25l). Besides, the release, and release of UCNP@α-CD simultaneously which can
internalization process was monitored to determine generate photothermal therapy. Therefore, the the synergy of
intracellular localization and distribution (Fig. 5). From the chemotherapy and photothermal treatment is achieved.
CLSM (confocal laser scanning microscopy) pictures,
a relatively little amount of bright red fluorescent spots were
We eventually researched the toxicity of the drug-loaded SHG
observed. However, strongerred fluorescence appeared in the in vivo. After staining with H&E in groups 1‒6 of all mice, there
cytoplasm after NIR irradiation. The result confirmed that the were no evident abnormalities or biological damage to the
SHG are stable enough in a complex cellular environment heart, liver, spleen, lung, and kidney at 14th day, demonstrating
before NIR irradiation. And when the azobenzene was low/no systemic toxicity of SHGs injection on the major organs
photoisomerized, the loaded SHG went through a gel-to-sol of mice (Fig. 7). We also carried out hematological analysis of
phase conversion led to more drugs release.
white blood cell (WBC), red blood cell (RBC), mean corpuscular
volume (MCV), hematocrit (HCT), hemoglobin (HGB), mean
In Vivo NIR-Responsive Treatment. Motivated by the above- corpuscular hemoglobin (MCH), mean corpuscular hemoglobin
described in vitro anticancer effect, the phototherapeutic concentration (MCHC), platelet (PLT), mean platelets volume
efficacy of the SHGs in vivo was studied further. HepG2 tumor- (MPV) and plateletcrit (PCT) on 14th day after treatment,
bearing nude mice subcutaneously as a tumor model, and all respectively. Encouragingly, these measures were within the
mice were divided into six groups (five mice in each group) at normal range (Fig. S27). The combination of these results
random for different experimental conditions: PBS injection confirmed that the SHG with/without drug loading possess
only (Group 1), NIR irradiation only (Group 2), UCNP@α-CD-E- good biocompatibility.
azo/XLG injection only (Group 3), UCNP@α-CD-E-azo/XLG
injection plus NIR irradiation (Group 4), DOX-UCNP@α-CD-E-
azo/XLG injection only (Group 5), and DOX-UCNP@α-CD-E-
azo/XLG injection plus NIR irradiation (Group 6) (Fig. S26a).
a
b
Fig. 6 (a) Relative body weights and (b) relative tumor volumes
of the mice in groups 1‒6. All mice were divided into six groups:
PBS injection only (Group 1), NIR irradiation only (Group 2),
UCNP@α-CD-E-azo/XLG injection only (Group 3), UCNP@α-CD-
E-azo/XLG injection plus NIR irradiation (Group 4), DOX-
UCNP@α-CD-E-azo/XLG injection only (Group 5), and DOX- Fig. 7 Histology staining of major organs (heart, liver, spleen,
UCNP@α-CD-E-azo/XLG injection plus NIR irradiation (Group 6). lung, and kidney) dissected from various treatments groups at
The NIR irradiation is 980 nm (1 W cm‒2) for 30 min.
14th day. All mice were arbitrarily divided into six groups: PBS
injection only (Group 1), NIR irradiation only (Group 2),
As shown in Fig. 6a, during the experiment period of 14 days, UCNP@α-CD-E-azo/XLG injection only (Group 3), UCNP@α-CD-
the weight changes of all mice in the control and treatment E-azo/XLG injection plus NIR irradiation (Group 4), DOX-
groups were negligible, indicating that these treatments had UCNP@α-CD-E-azo/XLG injection only (Group 5), and DOX-
less adverse effects. Tumor volumes in six groups were UCNP@α-CD-E-azo/XLG injection plus NIR irradiation (Group 6).
surveyed and mapped with time (Fig. 6b). In consistent with the The NIR irradiation is 980 nm (1 W cm‒2) for 30 min, scale bar =
in vitro results, whilst the tumors in Group 1-5 showed similar 50 µm.
pattern that was no much different. Remarkbly the inhibition
rate of DOX-UCNP@α-CD-E-azo/XLG injection plus NIR
irradiation (Group 6) was as as 0.23±1.27 % after 14 days.
Conclusions
Among all the groups, the tumor of Group 6 was the smallest
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In conclusion, our work presents synthesis method and
Journal Name
10, 3682; (b) Q. Chen, C. Wang, X. Zhang, G. Chen, Q. Hu, H.
View Article Online
Li, J. Wang, D. Wen, Y. Zhang, Y. Lu, G. DYaOnI:g1,0C.1.0J3ia9/nDg0,TJB. 0W09a3n5gK,
G. Dotti, Z. Gu, Nat. Nanotechnol., 2019, 14, 89; (c) J. Li, D. J.
Mooney, Nat. Rev. Mater., 2016, 1, 16071.
application prospect of UCNP@α-CD-E-azo/XLG SHGs featuring
reversible gel-to-sol phase transition driven by NIR irradiation,
as a release-controllable drug carrier for cancer treatment.
When the SHG was irradiated with NIR light, the UV light
emitted by UCNP caused the structure isomerization of
azobenzene, resulting in the escape from the cyclodextrin
cavity. The SHG showed low/no cytotoxicity and stability to
prevent early leakage. By injection to the tumor site directly and
then exposure to NIR light, the hydrogels can release drug
effectively and produce local heat by photothermal conversion.
Both in vitro and vivo experiments have proven its effective
inhibitory effect on tumors. By changing the dose or duration of
NIR exposure, the controllable amount of drug release can be
achieved. Considering the excellent drug loading and retaining
rate as well as the remotely controllable NIR-responsiveness
and remarkable chemotherapy and photothermal output and
efficacy, this work provides an exciting new candidate for
antitumor therapy and other site-specific treatments such as
dental or medical implant associated infections, especially
those requiring long-term, small-dose treatments in clinic.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank NNSFC (91860120) for financial support.
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We report injectable supramolecular hydrogels as high-load drug carriers, which
achieve the synergy of chemotherapy and photothermal treatment for cancer.