Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent

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Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent Nanoassemblies for Targeted Photothermal Cancer Therapy Ben Shi, Qinglong Yan, Jie Tang, Kai Xin, Jichao Zhang, Ying Zhu, Ge Xu, Rongchen Wang, Jian Chen, Wei Gao, Tianli Zhu, Jiye Shi, Chunhai Fan, Chunchang Zhao, and He Tian Nano Lett., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2018 Downloaded from http://pubs.acs.org on September 21, 2018

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Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent Nanoassemblies for Targeted Photothermal Cancer Therapy Ben Shi,†,# Qinglong Yan,‡,# Jie Tang,† Kai Xin,† Jichao Zhang, ‡ Ying Zhu,*,‡ Ge Xu,† Rongchen Wang,† Jian Chen,† Wei Gao,† Tianli Zhu, † Jiye Shi,‡ Chunhai Fan,*,‡‖ Chunchang Zhao*,†, He Tian† †

Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry

and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China. ‡

Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility,

CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China ‖

School of Chemistry and Chemical Engineering, and Institute of Molecular Medicine, Renji

Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China E-mails:

[email protected];

[email protected];

[email protected]

or

[email protected] #

These authors contributed equally.

ACS Paragon Plus Environment

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ABSTRACT. Near-infrared (NIR)-II fluorescence agents hold great promise for deep-tissue photothermal therapy (PTT) of cancers, which nevertheless remains restricted by the inherent non-specificity and toxicity of PTT. In response to this challenge, we herein develop a hydrogen sulfide (H2S)-activatable nanostructured photothermal agent (Nano-PT) for site-specific NIR-II fluorescence-guided PTT of colorectal cancer (CRC). Our in-vivo studies reveal that this theranostic Nano-PT probe is specifically activated in H2S-rich CRC tissues whereas nonfunctional in normal tissues. Activation of Nano-PT not only emits NIR-II fluorescence with deeper tissue penetration ability than conventional fluorescent probes but generates high NIR absorption resulting in efficient photothermal conversion under NIR laser irradiation. Importantly, we establish NIR-II imaging-guided PTT of CRC by applying the Nano-PT agent in tumor-bearing mice, which results in complete tumor regression with minimal non-specific damages. Our studies thus shed light on the development of cancer biomarker-activated PTT for precision medicine.

KEYWORDS. Nanostructured photothermal agent • hydrogen sulfide • activatable • theranostic • NIR-II fluorescence • tumor-specific.

Photothermal therapy (PTT) is rapidly emerging as a cancer treatment modality due to the unique advantages of simplicity, noninvasiveness, safety, and short treatment time.1-4 In PTT, photothermal agents are used to harvest light and convert photo-energy into heat for thermal ablation of cancer cells and tumors. So far, various types of near-infrared (NIR) absorbing agents have shown efficacy in in vivo cancer treatment, including gold nanoparticles,5-11 carbon materials,12-14 copper sulphide nanoparticles,15-20 and organic dyes21-30. To guide the NIR light specific irradiation of the tumor and the time for therapy, efforts have also been devoted to


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construction of imaging-guided PTT platforms which enable the destruction of cancer with specificity and sensitivity.31-34 However, despite these great advances, most of the existing PTT materials are not specifically related to cancer-associated events.35-36 That is, conventional photothermal agents would generate heat regardless of their distribution in cancers or normal tissues, resulting in the treatment-related toxicity and side effects on normal tissues. Here we aim to address this challenge by developing activatable PTT agents that generate photothermal effect only after specific activation in cancerous tissues while keep silent at noncancerous tissues, which should allow effective ablation of tumors but not normal tissues. In this study, we report the development of cancer biomarker-mediated in situ production of nanostructured NIR light-responsive photothermal agents for NIR-II fluorescence-guided therapy of colorectal cancer (CRC). CRC is one of the leading causes of mortality in the world.37-40 The management of colorectal cancer with conventional cancer therapies including chemotherapy and surgical resection always show undesired side effects and have limited effectiveness for patients with metastatic CRC.41-43 Consequently, it is of great importance and urgency to develop more effective cancer diagnostics and therapeutics. Emerging evidence has shown that overexpressed cystathionine-β-synthase (CBS) promotes increased H2S production in human colon cancers to support tumor cell bioenergetics, proliferation, migration and invasion.44 Especially, H2S as an appealing imaging target for identification of CRC has been recently established.45-49 Hence, we intend to investigate H2S as a potential pharmacological target for the imaging-guided treatment of CRC. NIR-II fluorescence imaging is used as it can provide deeper penetration in biological tissue and higher spatial resolution compared to traditional optical imaging techniques.50-55


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In our preliminary studies, we first tested our previously reported H2S-activated NIR probes, wherein N-ethyl-2,3,3-trimethylindolenine was appended to boron dipyrromethene (BODIPY) platform.49,56. Although high NIR absorption was introduced in the presence of H2S, these small molecules failed to effectively convert absorbed light into thermal energy. Considering that selfassembly of NIR light-absorbing molecules is beneficial to engineer photothermal materials,23,36 we reasoned that careful introduction hydrophilic unit to the aforementioned small molecules would generate nanostructured probes via self-assembly for H2S-mediated generation of NIR light-responsive photothermal transduction. To prove this concept, an H2S-responsive small molecule capable of self-assembly (SSS, Figure 1) was designed to comprise (1) a three triethylene glycol monomethyl ether chains functionalized phenyl ring as a hydrophilic tail to guide the self-assembly of SSS into nanostructured complexes (Nano-PT) with good aqueous solubility and (2) a monochlorinated BODIPY core as an activatable unit based on the thiol−halogen nucleophilic substitution with H2S. As demonstrated, such simple yet effective design of nanostructured assembly-based photothermal agent is crucial for the high light-to-heat energy conversion. In the absence of H2S, the Nano-PT gave minimal photothermal effect and showed the typical properties of BODIPY with absorption and emission at 540 and 589 nm, respectively. However, the introduction of H2S led to high NIR absorption around 790 nm, which not only caused a highly efficient light-to-heat energy conversion under irradiation with a 785-nm laser, but also afforded bright emissions within NIR-II region. Utilizing these promising properties, Nano-PT realized the imaging-guided effective photothermal ablation of CRC tumor.


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Figure 1. (a) The synthesis of compound SSS and H2S mediated transformation of SSS into an NIR-responsive photothermal agent. (b) Schematic illustration of Nano-PT as an activatable photothermal agent for NIR-II fluorescence-guided therapy of H2S-rich colorectal cancers. To synthesize materials with good water solubility and biocompatibility, we appended hydrophilic triethylene glycol chains functionalized semi-cyanine group to the hydrophobic BODIPY core via a vinylene bridge. This amphiphilic chemical structure ensures the spontaneous formation of nanostructured assemblies with well-defined size distribution in aqueous environments. As shown in Figure 1, the synthesis of the target compound SSS involved the alkylation of 2,3,3-trimethylindolenine with compound 1 to yield compound 2 and a subsequent condensation with aldehyde BODIPY. The chemical structure of SSS was identified by NMR spectroscopy and high resolution mass spectrometry. Compound SSS readily underwent self-assembly to form well-defined nanoparticles by dilution of the MeOH stock solutions with water due to the amphiphilic chemical structure. The size can be controlled by varying the concentrations of SSS as revealed by dynamic light scattering (DLS) experiments and transmission electron microscopy (TEM) images (Figure S1). For example, the DLS experiments showed that Nano-PT had hydrodynamic diameters of 8.4, 9.8, 11.0, 12.8 and 14.6 nm when SSS at concentrations of 10, 15, 20, 25 and 30 µM,


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respectively. In addition, Nano-PT exhibited good colloidal stability in PBS; after 14 days, the hydrodynamic diameter remained nearly unaltered (Figure S1). We first established that Nano-PT can indeed serve as a H2S-activated photothermal agent. As shown in Figure 2a and Figure S2, Nano-PT, containing various concentrations of SSS, gave H2S-dependent optical changes in PBS buffer solutions (pH 7.4). The introduction of NaHS (100 µM) reduced the original absorption peak at around 540 nm. Importantly, a strong NIR absorption at 790 nm (ε = 2×104 M-1 cm-1) was triggered by H2S, which guarantees the good photothermal conversion efficiency under NIR laser irradiation. In contrast, in the presence of other biologically relevant analytes, the optical spectrum remained essentially unchanged (Figure S3). The generation of NIR absorption at 790 nm was attributed to the thiol−halogen nucleophilic substitution (Figure S4). Considering the emergence of a new NIR absorbance upon interaction with H2S, we examined the photothermal effect of Nano-PT at concentrations of 10, 15, 20, 25 and 30 µM under the 785-nm NIR laser irradiation. Obviously, the temperature increase was dependent on H2S and SSS concentration as well as the laser power (Figure 2b-d). For example, after 10 min irradiation at 5.37 W/cm2, the temperature of the Nano-PT (SSS 20 µM) solution increased by 32 °C in the presence of H2S (Figure 2b). Repeated photothermal heating and cooling process (785-nm laser irradiation for 10 min, then naturally cooling to room temperature) showed that negligible changes were observed in the maximal temperature elevation during three cycles (Figure S5). In sharp contrast, the absence of H2S made the NanoPT solution no such thermal effect (Figure 2c). The difference in temperature increase of NanoPT at different conditions was also found to be intuitively visualized with the infrared (IR) thermal images (Figure 2e). These results demonstrated that H2S plays a vital role in transformation of SSS into an NIR-responsive photothermal agent. The H2S-activated


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photothermal conversion efficiency (η) of Nano-PT, exposure to a 785-nm laser at the power density of 5.37 W/cm2, was then determined to be approximately 27.8% (Figure S5), indicative that Nano-PT is promising for activatable PTT applications. For accurate cancer diagnosis, it is imperative to develop imaging probes with activatable fluorescence signals as such probes undergo fluorescence evolution only upon interaction with specific biological targets, thus amplifying signals from the target and minimizing background signals.57-60 We then explored the feasibility of Nano-PT as an activatable fluorescent probe under physiological condition. As shown in Figure 2f, the addition of H2S elicited a timedependent fluorescence increase within NIR II regions which leveled off in 20 min and eventually triggered a bright NIR-II image (the relative low quantum yield of 0.0034% due to self-quenching in Nano-PT) under 810-nm laser irradiation (Figure 2f inset). Furthermore, NanoPT showed highly sensitive response to H2S with a detection limit of 106 nM (Figure S6). These results indicated that Nano-PT is a H2S-activated probe with NIR-II emissions, enabling NanoPT to be a reliable tool for cancer diagnosis and imaging-guided cancer treatment. Although several NIR-II materials based on organic dyes are now available for in vivo imaging,54 their applications as photothermal agents are scarcely studied.


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Figure 2. (a) Time-dependent absorption changes of Nano-PT (20 µM SSS) in the presence of 100 µM NaHS. (b) Laser-power-dependent temperature changes of Nano-PT (20 µM SSS) in the presence of NaHS (100 µM). (c) Temperature change curves of PBS and Nano-PT (20 µM SSS) in the absence and presence of NaHS (100 µM) upon 785-nm laser irradiation (5.37 W/cm2). (d) Temperature elevation for Nano-PT at different concentrations in the presence of NaHS (100 µM) under 785-nm laser irradiation (5.37 W/cm2). (e) Representative IR thermal images of Nano-PT (20 µM SSS) in the presence of NaHS (100 µM) under 785-nm laser irradiation. (f) Time-dependent NIR-II emission spectra of Nano-PT (20 µM SSS) in the presence of 100 µM NaHS, λex = 790 nm. Inset is the photograph of the H2S-activated NIR-II emission. Encouraged by the capability of Nano-PT as an activatable photothermal agent, we then evaluated the capability of Nano-PT for thermal ablation of cancer cells under laser irradiation. The in vitro PTT efficacy of Nano-PT to the human colorectal cancer cells (HCT116) were examined due to high levels of H2S in HCT116 cells. As seen from the standard MTT assay (Figure S7a), in the absence of laser light, Nano-PT showed negligible cytotoxicity at


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concentrations below 20 µM. In contrast, high cytotoxicity was observed when HCT116 cells were treated with Nano-PT and 785-nm laser irradiation simultaneously. Notably, the viability of cells without Nano-PT was not affected under light irradiation. We further performed staining experiments with calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) to examine the cell death induced by Nano-PT mediated PTT. As shown in Figure 3a, HCT116 cells treated with either Nano-PT or 785-nm laser alone showed only strong green fluorescence of calceinAM, indicating that most of the cells are viable. However, treatment of cells with Nano-PT (20 µM) plus 785-nm laser introduced PI-positive red signals and loss of the green fluorescence for calcein-AM, suggesting high cell mortality rate. To prove that Nano-PT is specifically activated by H2S for photothermal ablation of cells, control experiments with H2S-defficient HepG2 cells were performed. It was found that Nano-PT showed minimal dark cytotoxicity and low photocytotoxicity in HepG2 cells (Figure S7b), implying that Nano-PT was silent in the absence of H2S. These results clearly demonstrated that Nano-PT is a new class of ativatable PTT agent in H2S-rich cancer cells. Imaging-guided PTT is believed to effectively minimize the side-effects and optimize the therapeutic outcome.1-4,31-34 NIR-II fluorescence imaging was thus used to track the activation of Nano-PT in CRC. The HCT116 tumor-bearing mouse were treated with Nano-PT and subjected to in vivo imaging at various times. As shown in Figure 3b, bright NIR-II emission in the tumor gradually increased and reached to the maximum within 2 h post-injection, suggesting that NIRII Imaging can guide the right time point for PPT treatment. Notably, negligible background fluorescence was observed. Region of interest measurements showed that the NIR-II signal ratio between the tumor and background at 2 h was approximately 8.3±0.5 (Figure S7c). In contrast, minimal NIR-II signals could be noted in the normal site injected with the probe, displaying a


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much weaker signal-to-background ratio. These results demonstrated that Nano-PT can be specifically activated in H2S-rich colorectal cancers. Combined, NIR-II Imaging provides valuable information for both diagnosis and therapeutic administration.

Figure 3. (a) Confocal fluorescence images of Calcein AM/PI stained HCT116 cells with different treatments. Scale bars: 50 µm. The laser power was 2.05 W/cm2. (b) In vivo NIR-II imaging of tumor-bearing mice using Nano-PT (100 nmol SSS). Nano-PT in PBS was injected subcutaneously into the tumor regions and normal sites of living mice, and images were taken at various time points after injection. (c-f) Infrared thermal images of HCT116 tumor-bearing mice under continuous NIR laser irradiation: (c) No administration of probes; (d) Probe-treated mice


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in the normal sites; (e) Probe-treated mice in the tumor regions; (f) The mean temperature as a function of irradiation time. Laser irradiation was performed at 2 h post administration of NanoPT. Encouraged by the NIR-II Imaging data that afforded the right time point and specific site for laser irradiation, we next evaluated in vivo tumor inhibition effect with Nano-PT by irradiating with a 785 nm laser (1.66 W/cm2) at 2 h post-injection. For in vivo PTT treatment, HCT116 tumor-bearing mice were divided into four groups (6 mice per group): untreated mice (Group 1), mice with Nano-PT injection into tumors but no laser irradiation (Group 2), mice with laser irradiation but no Nano-PT administration (Group 3), mice with both Nano-PT injection into tumors and laser irradiation (Group 4). Mice with both Nano-PT injection into normal sites and laser irradiation were also studied to confirm the inactive feature of Nano-PT in H2S-deficient non-cancerous tissues. For mice with both Nano-PT injection into tumors and laser irradiation, the tumor temperature rapidly increased to approximately 60.9 °C under the NIR laser irradiation for 10 min. In comparison, the tumor temperature of mice treated with only irradiation showed slight changes (Figure 3c). It should be noted that the normal sites injected with Nano-PT also showed only mild temperature changes under the same irradiation (Figure 3d). These results demonstrated that Nano-PT can only be activated within tumors for efficient photothermal conversion, representing a promising activatable PTT agent for tumor in vivo. The in vivo treatment outcome of the photothermal therapy with Nano-PT was then assessed by continuously monitoring the tumor sizes and body weights of HCT116 tumor-bearing mice for 15 days (Figure 4 and Figure S8). Experimental data showed that tumor growth inhibition was not observed in mice treated with only NIR irradiation, indicating that 785-nm laser irradiation had no antitumor efficacy. Moreover, the injection of Nano-PT into tumors but no


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laser irradiation did not give obvious suppression of the tumor growth, suggesting that Nano-PT has negligible dark toxicity. Thus the tumor volume of mice in these two groups showed negligible difference when compared to those of the untreated mice (Figure 4a). In marked contrast, tumors of mice treated by Nano-PT and laser irradiation simultaneously were successfully ablated (Figure 4b). The mice of this group experienced nearly complete tumor regression within 15 days. Such an excellent antitumor efficacy was further confirmed by the average weights of excised tumors and the corresponding intuitively visualized photographs (Figure 4c). Interestingly, no obvious tissue damage was noted when the normal sites injected with Nano-PT were performed laser irradiation (Figure S8), manifesting that Nano-PT is deactivated in normal tissue and thus no effective photothermal behavior. From the fluorescence TUNEL staining (Figure 4d and Figure S9), significant cancer cells apoptosis (green fluorescence) was noticed only in the tumor with both Nano-PT administration and laser irradiation, but not in other treatment groups. Importantly, the hematoxylin and eosin (H&E) staining clearly showed typical necrotic areas in the tumors while no noticeable histopathological damage in the surrounding normal areas of mice treated by Nano-PT and laser irradiation (Figure S10a). In addition, minimal histopathological damage (Figure S10b) was observed in the H&E staining of organs including heart, liver, spleen, lung, and kidney, indicative of the biocompatibility of Nano-PT. The biosafety of Nano-PT was further demonstrated by blood biochemistry analysis wherein no abnormal results were observed (Figure S11). Finally, no obvious changes of the body weights were observed in mice with various treatments (Figure 4e), suggesting the low side toxic effect of PTT by Nano-PT. These results clearly indicate that Nano-PT can be effectively converted to a photothermal agent in H2S-rich HCCT116 tumor for PTT treatment of cancer.


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In summary, we have developed an activatable theranostic agent for NIR-II fluorescenceguided photothermal therapy of cancers. The designed molecule readily undergoes self-assembly to form well-defined nanoparticles (Nano-PT) with good water solubility and biocompatibility. Nano-PT can serve as a H2S-activated photothermal agent, showing a strong NIR absorption at 790 nm and good photothermal conversion efficiency in the presence of H2S. Thus, H2S-rich cancer cells can be selectively ablated with this activatable PTT agent. In addition, Nano-PT is a H2S-activated probe with NIR-II emissions, which is ideal for cancer diagnosis and imagingguided cancer treatment due to the capability of NIR-II imaging for supplying high-resolution bioimaging with deep-tissue penetration. By using NIR-II fluorescent imaging, the specific activation of Nano-PT in colorectal cancers is successfully tracked. The in vivo tumor inhibition reveals that Nano-PT can be effectively converted to a photothermal agent in H2S-rich HCCT116 tumor for PTT treatment of cancer. To our knowledge, the study represents the first example of cancer biomarker-mediated in situ transformation of synthetic molecules into NIR lightresponsive photothermal agents for NIR-II fluorescence-guided therapy of CRC. We believe that this design approach will advance the development of materials for tumor-specific photothermal therapy with minimized toxicity and side effects on normal tissues.


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Figure 4. In vivo treatment outcome of the photothermal therapy with Nano-PT (100 nmol SSS) in HCT116 tumor-bearing mice. (a) Tumor growth curves of mice in different groups. (b) Representative photos of mice in different groups during the Nano-PT mediated PTT process. Red circles indicate the location of tumor. (c) Ratio of tumor weight in different groups relative to that in untreated mice obtained on day 15 and representative photographs of tumor tissues on day 15. ***p < 0.001, **p < 0.01. (d) The fluorescence TUNEL staining analysis of the tumor


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tissues after treatment. Scale bar: 50 µm. (e) Body weight change curves in different groups of mice. ASSOCIATED CONTENT Supporting Information. Detailed synthesis and characterization, experimental procedures, supplementary figures. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] * E-mail: [email protected] * E-mail: [email protected] or [email protected] Author Contributions #

B. S. and Q. Y. contributed equally.

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge the financial support by the National Key R&D Program of China (2016YFA0400900), National Science Foundation of China (grant numbers 21672062, 11675251, 21390414), and the Key Research Program of Frontier Sciences, CAS (Grant NO. QYZDJ-SSW-SLH031).


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for TOC only


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Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent

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