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Communication

Photodynamic Therapy www.advmat.de

Responsive Assembly of Upconversion Nanoparticles for


pH-Activated and Near-Infrared-Triggered Photodynamic
Therapy of Deep Tumors
Fangyuan Li, Yang Du, Jianan Liu, Heng Sun, Jin Wang, Ruiqing Li, Dokyoon Kim,
Taeghwan Hyeon, and Daishun Ling*

clinical application of PDT.[2] Recently,


Upconversion nanoparticle (UCNP)-mediated photodynamic therapy has lanthanide ion-doped upconversion nano-
shown great effectiveness in increasing the tissue-penetration depth of particles (UCNPs),[3] which absorb near-
light to combat deep-seated tumors. However, the inevitable phototoxicity infrared (NIR) light and subsequently emit
to normal tissues resulting from the lack of tumor selectivity remains as a the high-energy visible light,[4] have been
utilized as nanotransducers for deep-tissue
major challenge. Here, the development of tumor-pH-sensitive photodynamic
PDT in vivo.[5] However, such PDT agents
nanoagents (PPNs) comprised of self-assembled photosensitizers grafted pH- still have side effects due to deficiencies in
responsive polymeric ligands and UCNPs is reported. Under neutral pH con- selective accumulation at tumor sites and
ditions, photosensitizers aggregated in the PPNs are self-quenched; however, unavoidable activation of photosensitizers
upon entry into a tumor microenvironment with lower pH, the PPNs not only under white-light exposure or by self-
catalyzed reactions.[6] As a result, patients
exhibit enhanced tumor-cell internalization due to charge reversal but also are
are required to avoid exposure to daylight,
further disassembled into well-dispersed nanoparticles in the endo/lysosomes which increases the burden of patients
of tumor cells, enabling the efficient activation of photosensitizers. The results undergoing the PDT treatment.[7] Recently,
demonstrate the attractive properties of both UCNP-mediated deep-tissue various photo­ sensitizers (PSs)[8] capable
penetration of light and high therapeutic selectivity in vitro and in vivo. of selective activation by tumor-associated
stimuli,[9] such as pH,[10] H2O2,[11] glu-
tathione,[12] and enzymes,[13] have been
developed. Although triggering sources
Photodynamic therapy (PDT) has been widely applied to onco- of visible light are still involved, engineered systems relying
therapy because of its minimally invasive nature and spatiotem- on additional internal stimuli would confer greatly enhanced
porally controlled treatment capability.[1] However, the limited safety for PDT. However, thus far, there are few studies focused
tissue-penetration depth of visible light prevents the broad on internal-stimuli-responsive PDT agents based on UCNPs,
which would be very beneficial for selective PDT of deep
tumors, given that they would only be activated at tumor sites
Dr. F. Li, Y. Du, H. Sun, J. Wang, R. Li, Prof. D. Ling and subsequently triggered by NIR light.
Institute of Pharmaceutics Here, we developed tumor-pH-sensitive photodynamic
College of Pharmaceutical Sciences nanoagents (PPNs) comprised of self-assembled photosen-
Zhejiang University
sitizers grafted pH-responsive polymeric ligands (PPLs) and
Hangzhou, Zhejiang 310058, P. R. China
E-mail: [email protected] UCNPs. The PPNs are negatively charged without any discern-
Dr. J. Liu, Dr. D. Kim, Prof. T. Hyeon ible photo­activity at normal blood pH of ≈7.4, but can quickly
Center for Nanoparticle Research switch their surface charge from negative to positive at an
Institute for Basic Science (IBS) extracellular tumor pH of ≈6.5, and are further disassembled
Seoul 08826, Republic of Korea into individual UCNPs at intracellular tumor endo/lysosome
Prof. T. Hyeon pH (≈5.5). This disassembly process promotes the dissociation
School of Chemical and Biological Engineering
Seoul National University of the aggregated PSs (self-quenched state) into extended free
Seoul 08826, Republic of Korea molecules (dequenched state), enabling significantly enhanced
Prof. D. Ling photo­ activity of the PSs (Figure 1a). Upon NIR irradiation,
Key Laboratory of Biomedical Engineering of the Ministry of Education upconverted emission light from the UCNPs can induce the
College of Biomedical Engineering & Instrument Science photoactivity of the free PSs in acidic tumor microenvironment
Zhejiang University
(Figure 1b). Moreover, the strong upconversion luminescence
Hangzhou, Zhejiang 310027, P. R. China
(UCL) from the PPNs can be utilized for imaging-guided PDT.
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adma.201802808. Based on their unique properties involving pH-activated struc-
tural switching, we successfully demonstrate the selective PDT
DOI: 10.1002/adma.201802808 of deep-seated tumors.

Adv. Mater. 2018, 1802808 1802808 (1 of 7) © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Figure 1. Design and mechanism associated with tumor-pH activation of PPNs. a) Schematic illustration of pH responsive ligand-assisted assembly
of UCNPs. b) Schematic representation of tumor-pH-responsive deep tissue PDT.

To fabricate the PPNs, α-NaYF4:Yb(80%),Er(2%)@CaF2 (API), 3-phenyl-1-propylamine (PPA), and Ce6. The assembly
core@shell nanoparticles were selected as nanotransducers for of UCNP/PPLs was achieved using a ligand-assisted strategy.
PDT, because the red-emission intensity from these UCNPs is First, UCNPs dispersed in chloroform were added dropwise
15 times higher than well-known β-phase core/shell UCNPs to the acid–water solution containing PPLs. Upon ultrasonica-
and is suitable for the activation of PS chlorin e6 (Ce6).[14] To tion, the formation of a nanoemulsion occurred, resulting in
impart PPNs with responsiveness to tumor acidic microenviron- effective encapsulation of the UCNPs. The mixture was then
ment, PPLs were prepared by derivatizing poly(ethylene glycol)− stirred at room temperature for 1 h before the complete evapo-
poly(β-benzyl-l-aspartate) with 1-(3-aminopropyl) imidazole ration of chloroform at 60 °C. Second, Pluronic F68 (F68), an

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Figure 2. Characterization of PPNs. a) TEM image of PPNs at pH 7.4. b) TEM image of PPNs at pH 5.5. c) Changes in the zeta potential of PPNs at
indicated pH values. d) Particle size distribution of PPNs at selected pH values. e) Fluorescence intensity of Ce6 from PPNs at different pH values
(Ex = 400 nm, Em = 670 nm). f) pH-dependent changes in transmittance of PPNs. Inset: photographs of PPNs at different pH values. g) UCL spectrum
of α-NaYF4:Yb(80%), Er(2%)@CaF2 core@shell nanoparticles and absorbance spectrum of Ce6. h) Changes in the DPBF absorbance spectra in the
presence of PPNs at pH 5.5 under 980 nm laser irradiation over various time durations. i) pH-dependent DPBF absorbance in the presence of PPNs
or PPLs under 980 nm laser irradiation at different pH values. Error bars represent standard deviation (n = 3 per group).

FDA-approved surfactant,[15] was added to the mixture con- ≈120 nm (Figure 2d) at pH 7.4, where the fluorescence inten-
taining the PPLs-modified UCNPs to confer the assembled sity and photoactivity of Ce6 in PPNs is largely quenched due
PPNs with colloidal stability in a neutral solution. Finally, excess to their close proximity to one another (Figure 2e).[16,17] Once
ligands were removed by centrifugation, and the obtained nano- the pH decreases to ≈6.5 in the tumor microenvironment,
agents were dispersed in phosphate-buffered saline (PBS). More PPNs quickly reverse their charge to positive because of ioniza-
detailed synthetic routes and characterizations are described in tion of the imidazole groups (pKa ≈ 6.8). This charge reversal
the supporting information (Figures S1–S8, Supporting Infor- not only facilitates the uptake of the positively charged PPNs
mation). The pH-insensitive photodynamic nanoagents (PIPNs) to tumor cells,[18] but also significantly enhances the electro-
were prepared as a control using a similar synthetic process, but static repulsive force between the UCNPs inside the PPNs. As
utilizing imidazole-free ligands. a result, PPNs begin to swell and partially dissociate (Figure 2d;
As shown in transmission electron microscopy (TEM) Figure S9, Supporting Information), and when the pH fur-
images (Figure 2a,b; Figure S9, Supporting Information), sev- ther decreases to 5.5, the hydrophobic interactions inside the
eral UCNPs are assembled to form PPNs at pH 7.4 and disas- PPNs become weaker than the repulsive force between ion-
sembled into isolated UCNPs at acidic condition. The PPNs are ized unimers, leading to the complete dissociation of the PPNs
negatively charged (Figure 2c) with a hydrodynamic diameter of (Figure 2b,d). As pH decreases from 7.4 to 5.5, the average

Adv. Mater. 2018, 1802808 1802808 (3 of 7) © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Figure 3. pH-dependent interactions with cells in vitro. a) Confocal laser scanning microscopic studies to demonstrate the cellular uptake of PPNs
and PIPNs under mild acid environment (pH 6.5). Cells stained with DAPI are shown in blue, and fluorescence signals from Ce6 in PPNs or PIPNs are
shown in red (scale bar = 50 µm). b) CCK-8 assays of A549 cells exposed to PIPNs without 980 nm laser irradiation at either pH 6.5 or 7.4. c) CCK-8
assays of A549 cells exposed to PIPNs with 980 nm laser irradiation at either pH 6.5 or 7.4. d) CCK-8 assays of A549 cells exposed to PPNs without
980 nm laser irradiation at either pH 6.5 or 7.4. e) CCK-8 assays of A549 cells exposed to PPNs with 980 nm laser irradiation at either pH 6.5 or 7.4.
(the indicated concentrations represent the concentration of Ce6 in PIPNs or PPNs). The values represent mean ± standard deviation (SD). (n = 6 per
group). *P < 0.05 as compared to other groups according to multiple t tests.

distance between Ce6 molecules increases, resulting in the absorbance of PPNs is gradually declined (Figure S10, Sup-
recovery of Ce6 fluorescence intensity and photoactivity of porting Information) due to the increased transmittance
PPNs (Figure 2e). The disassembly process is further studied (Figure 2f), while the UCL from PPNs is increased due to the
by monitoring spectral changes. As pH value decreases, the reduced resonance energy transfer (Figure S10, Supporting

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Figure 4. UCL-imaging-guided PDT in vivo. a) In vivo UCL images of mice injected with PPNs, showing corresponding color-mapping-merged images
(upper) and those involving tumors covered with pork tissues (lower). b) Relative tumor volume (Vd/V0) changes in the indicated groups during treat-
ment. *P < 0.05 as compared to PBS groups according to a one-way analysis of variance (ANOVA) test. c) Body weight changes in the indicated groups
during treatment. Data represent mean ± standard deviation (SD) (n = 4 mice per group). d) Pathological analysis of tumor-inhibitory effects. Repre-
sentative H&E, TUNEL, Ki67, and CD31 staining of tumor sections collected from different groups at 14 days post-PDT treatment (scale bar = 100 µm).

Information). All these results demonstrate the pH-responsive reversible (Figure 2f). By contrast, the size and fluorescence
assembly/disassembly property of PPNs. It is worth men- properties of PIPNs are not dependent on pH (Figure S11, Sup-
tioning that such assembly/disassembly processes are fully porting Information).

Adv. Mater. 2018, 1802808 1802808 (5 of 7) © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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We then investigated whether the UCL from the UCNPs can NIR- or red-light-irradiated PPNs, whereas cells in both the PBS
excite free Ce6 molecules under acidic conditions. As shown in and PIPN groups largely retained their normal morphology.[20]
Figure 2g, red emission from UCNPs matches one of the absorb- Importantly, we were still able to observe clear cancer cell damage
ance peaks of Ce6, indicating that UCNPs can be potentially used for the group where tumors were covered with 7-mm-thick pork
as transducers for Ce6 activation. Moreover, we used 1,3-diphe- tissues and irradiated with NIR. By contrast, the pork-tissue-
nylisobenzofuran (DPBF) to investigate the NIR-triggered sin- covered red-light-irradiation group did not show any obvious
glet-oxygen-generation of PPNs.[19] In aqueous solution (pH 7.4) cell damage, again indicating that NIR-light excitation is prefer-
containing PPNs or PPLs, the DPBF-absorption intensity shows able for deep-tumor PDT. Additionally, terminal deoxynucleotidyl
only a slight decrease under NIR irradiation (Figure S12, Sup- transferase dUTP nick end labeling (TUNEL), Ki-67, and CD31
porting Information). In sharp contrast, the DPBF-absorption immunolabeling reveal enhanced cancer cell apoptosis and inhi-
intensity continuously decreases along with increasing NIR dura- bition of proliferation following PPNs + Pork + NIR treatment rel-
tions (pH 5.5) (Figure 2h,i). This data reflect the pH-activated ative to those observed following PPNs + Pork + Red treatment.
PDT on/off behavior of the PPNs upon repeatedly switching pH All these results clearly show that NIR-triggered pH-sensitive
between 5.5 and 7.4 (Figure S10d, Supporting Information). PDT has the highest anticancer efficacy than other treatments.
To validate the feasibility of using PPNs for pH-activated In conclusion, we developed a pH-activated and NIR-
and NIR-triggered PDT, we incubated A549 cells with PPNs or triggered photodynamic nanoagent based on the controlled
PIPNs. As shown in Figure 3a, more intense Ce6 fluorescence assembly of photosensitizers grafted pH-responsive poly-
signal is observed in the cytoplasm of PPNs-treated A549 cells meric ligands and UCNPs for the targeted PDT of deep-seated
as compared with that of PIPNs. Moreover, the signal is more tumors. Under a mildly acidic tumor microenvironment, PPNs
intense for the PPNs-treated cells incubated at pH 6.5 rather charge reversal efficiently enhanced their cellular internaliza-
than pH 7.4 (Figure S13, Supporting Information). These tion. Subsequently, complete PPNs disassembly at lower endo-
results show that our PPNs are efficient for tumor-cell inter- somal pH levels facilitated the photoactivation of the polymeric
nalization under mild acidic conditions. Furthermore, we evalu- PSs. Both in vitro and in vivo results indicate that these PPNs
ated pH-responsive PDT efficiency in vitro by first verifying that can serve as a potentially new class of PDT agent for use in
both PPNs and PIPNs exhibit no noticeable cytotoxicity to cells future cancer theranostics based on their ability to overcome
without laser irradiation at either pH 6.5 or 7.4 (Figure 3b,d). limitations associated with conventional PSs, such as limited
Regardless of different pH values, there is no significant differ- tissue-penetration depth, deficiencies in tumor-cell-targeting
ence in cell viability under NIR irradiation for the PIPNs-treated ability, and inevitable side effects observed in normal tissues.
cells (Figure 3c). In sharp contrast, PPNs-incubated cells show
significantly elevated death rates at pH 6.5 as compared with
the cells at pH 7.4 (Figure 3e). These results clearly demonstrate Supporting Information
that both enhanced cell internalization and acidic pH-activated Supporting Information is available from the Wiley Online Library or
disassembly of PPNs contribute to the enhanced PDT in vitro. from the author.
We then assessed the potential of PPNs for in vivo deep tissue
PDT by intratumorally injecting PPNs into A549 tumor-bearing
nude BALB/c mice. As shown in Figure 4a, strong UCL signals Acknowledgements
were observed at the tumor sites, even at 8 h postinjection, clearly F.L., Y.D., and J.L. contributed equally to this work. The authors acknowledge
indicating the high uptake efficiency of the PPNs in the tumor. financial support by the National Key Research and Development Program of
Moreover, the strong UCL signal could still be detected, even when China (2016YFA0203600), the National Natural Science Foundation of China
a 7-mm-thick pork tissue was placed over the tumor to simulate a (51503180, 51703195, and 51611540345), “Thousand Talents Program”
deep tumor, indicating that PPNs could be used for deep-seated for Distinguished Young Scholars (588020*G81501/048), Fundamental
Research Funds for the Central Universities (520002*172210161), and
tumor imaging. In addition, such a strong UCL signal will greatly
the Research Center Program for the Institute of Basic Science in Korea
facilitate the focus of NIR light only on tumor sites and enhance (IBS-R006-D1). The animal experimental protocol was performed with the
the accuracy of PDT. We then evaluated the antitumor efficacy of approval of the Institutional Animal Care and Use Committee of Zhejiang
the PPNs for deep-seated tumors by comparing relative tumor size University School of Medicine (Protocol No. ZJU20170739) and followed
upon light irradiation with that of the control group. As shown in the National Guidelines for Animal Protection.
Figure 4b, both the NIR- and red-light-irradiated groups showed
similarly high antitumor effects, whereas those treated with either
PBS or PIPNs showed no obvious antitumor effects. Compared Conflict of Interest
with PPNs + Pork + Red group, the PPNs + Pork + NIR group
The authors declare no conflict of interest.
exhibited higher antitumor efficacy, with a relative tumor volume
of 6.9 versus 11.8 at 14 days postinjection, indicating that NIR is
more effective for deep tumor treatment. Additionally, the body Keywords
weight of mice did not show obvious changes (Figure 4c), indi-
nanoassembly, photodynamic therapy, pH-responsive, theranostics,
cating the high biocompatibility of the PPNs.
upconversion nanoparticle
Furthermore, therapeutic efficacy in terms of cancer cell death
was evaluated by histological analysis of tumor tissues (Figure 4d). Received: May 2, 2018
Images of tumor slices stained with hematoxylin and eosin Revised: June 10, 2018
showed significant cancer-cell damage in the groups harboring Published online:

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