Amphiphilic redox-sensitive NIR BODIPY nanoparticles for dual-mode imaging and photothermal therapy

Accepted Manuscript Amphiphilic redox-sensitive NIR BODIPY nanoparticles for dual-mode imaging and photothermal therapy Xin Wang, Wenhai Lin, Wei Zhang, Cheng Li, Tingting Sun, Guang Chen, Zhigang Xie PII: DOI: Reference:

S0021-9797(18)31245-1 https://doi.org/10.1016/j.jcis.2018.10.051 YJCIS 24206

To appear in:

Journal of Colloid and Interface Science

Received Date: Revised Date: Accepted Date:

19 July 2018 12 October 2018 17 October 2018

Please cite this article as: X. Wang, W. Lin, W. Zhang, C. Li, T. Sun, G. Chen, Z. Xie, Amphiphilic redox-sensitive NIR BODIPY nanoparticles for dual-mode imaging and photothermal therapy, Journal of Colloid and Interface Science (2018), doi: https://doi.org/10.1016/j.jcis.2018.10.051

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Amphiphilic redox-sensitive NIR BODIPY nanoparticles for dual-mode imaging and photothermal therapy Xin Wang,a, b Wenhai Lin,b, c,* Wei Zhang,b, c Cheng Li,d Tingting Sun,b, c Guang Chen,a,* Zhigang Xieb,* a

Department of Thyroid Surgery, The First Hospital of Jilin University, 71 Xinmin

Street, Changchun, Jilin 130021, P. R. China. b

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of

Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China. c

University of Chinese Academy of Sciences, Beijing 100049, P. R. China

d

Department of Cardiovascular Medicine, The First Hospital of Jilin University, 71

Xinmin Street, Changchun, Jilin 130021, P. R. China.

KEYWORDS: near-infrared fluorescence imaging, photoacoustic imaging, photothermal therapy, redox-sensitivity, amphiphilic nanoparticles

ABSTRACT Theranostics, integrating tumor treatment and diagnosis concurrently, has become an emerging and meaningful strategy in cancer therapy. In this work, an amphiphilic redox-sensitive near-infrared (NIR) BODIPY dye, which could be formed into

nanoparticles (PEG-SS-BDP NPs) by self-assembly, was synthesized and possessed good capability of photothermal therapy (PTT), near-infrared fluorescence (NIRF) imaging, photoacoustic (PA) imaging and drug loading. The stable nanoparticles could be dissociated to turn on NIRF due to the rift of embedded disulfide bonds by glutathione (GSH). The enhanced fluorescence in vitro could be observed via confocal laser scanning microscopy (CLSM) after adding GSH, confirming the redox-sensitivity of disulfide bonds. NIRF and PA imaging demonstrated active accumulation in tumor and good imaging effect. At last, PEG-SS-BDP NPs could significantly suppress tumor growth in vivo upon irradiation. The amphiphilic redox-sensitive BODIPY nanoparticles provide a promising design strategy to formulate multifunctional stimuli-responsive theranostic nanoplatforms.

1. INTRODUCTION Photothermal therapy (PTT), which utilizes photo-sensitive reagents to reap light energy and convert it into thermal energy, could efficiently lead to the thermal ablation of cancer cells and has been applied into cancer treatment.1-4 PTT is attractive and promising due to its non-invasive and minimal side effects compared to other cancer therapies such as surgery, chemotherapy and radiotherapy. 5-10 For decades, scientists are enthusiastic about developing photothermal reagents and have made a lot of progress.11-13 It’s well known that the use of photothermal reagents with the absorbance in NIR region (650-950 nm) could minimize the interference of body composition such as blood and tissues. 6, 14, 15 Among various photothermal reagents,

Boron−dipyrrome-thenes (BODIPY), which possess various advantages like high photoluminescence quantum yields and stability in physiological environment, have been applied in photodynamic therapy (PDT), PTT and imaging. 16-26 However, how to achieve multifunctional BODIPY for imaging and PTT/PDT remains a huge challenge. More importantly, BODIPY is hydrophobic and water-insoluble, which limits its application in biological field.18, 27 Therefore, it is extremely significant to find a simple way to increase the solubility of BODIPY in aqueous media. Nanoparticles could load hydrophobic compounds via physical package or chemical bonding, which have been widely applied into drug delivery.

28-36

PEGylation has been regarded as a simple and efficient way to modify hydrophobic drugs and imaging agents, and the obtained amphiphilic compounds could form into stable nanoparticles in water. Therefore, it’s feasible and practical to construct multifunctional BODIPY nanoparticles for theranostics via PEGylation.37-41 It is reported that the concentration of GSH in tumor is around 4-fold higher than that in normal tissues, and its accumulation in cytoplasm (0.5–10 mM) is far more than that in extracellular environment (2-20 μM).42 GSH could induce intracellular reduction and help the drug release within cells, demonstrating that GSH could be applied as intracellular reduction-responsive irritant.43-45 Disulfide bonds were usually used as key component in reduction responsive drugs, which offered an effective approach to improve biodegradability of nanoparticles.46-48 In this work, we designed and synthesized an amphiphilic redox-responsive NIR BODIPY dye, which could be formed into stable nanoparticles in aqueous solution via

self-assembly and be used for tumor theranostics. Polyethylene glycol (PEG) was linked with BODIPY through disulfide bond, and the redox-sensitive disulfide bond could accelerate the dissociation of nanoparticles to turn on the NIRF fluorescence. The formed nanoparticles (PEG-SS-BDP NPs), as a multifunctional agent, could be used for PTT, PA and NIRF imaging and show promising effects in treatment and diagnosis of cancer simultaneously.

2. METHODS 2.1 Materials. Glutathione (GSH) was purchased from Shanghai Yuanye Biological Technology Co., Ltd. Live/Dead cells staining kit was purchased from Nanjing KeyGen Biotech. Co., Ltd. (China). All of the other chemicals were obtained commercially and used without further purification, unless otherwise noted. The instruments used during the whole experiment were listed in our previous work. 49 2.2 Synthesis of PEG-SS-BDP, preparation of PEG-SS-BDP NPs and PTX@PSB NPs, cellular uptake and photothermal experiments. The entire process is clarified in electronic supplementary information. 2.3 Animal experiments. Animal experiments were strictly conformed to the provision of Research Animals established by Jilin University Studies Committee. Nude mice (6 weeks old) bearing human cervical carcinoma (HeLa) tumors in the left armpit were pretreated intratumorally with PEG-SS-BDP NPs (1 mg/mL, 200 μL) for 12 h and then used to

PA imaging. Female Kunming mice (6 weeks old) bearing U14 tumor in the left armpit were applied to NIRF imaging and PTT. Mice were injected with PEG-SS-BDP NPs (1 mg/mL, 200 μL) intratumorally and intravenously respectively and imaged at 1 h, 6 h, 12 h, 24 h, 36 h and 72 h after drug administration. Then the mice were sacrificed and dissected to obtain the NIRF imaging of tumor, heart, liver, spleen, lung and kidney. As for PTT, mice were separated into four groups: (1) Control, no treatment; (2) Light; (3) PEG-SS-BDP NPs (1 mg/mL, 200 μL); (4) PEG-SS-BDP NPs (1 mg/mL, 200 μL) + Light. The mice in group 3 and 4 were injected intratumorally, and after 2 h group 2 and 4 were irradiated (808 nm, 0.5 W/cm2) for 20 min and the diameter of light spot was 1.5 cm.

3. RESULTS AND DISCUSSION 3.1 Synthesis and Preparation of PEG-SS-BDP NPs. First, an amphiphilic NIR BODIPY dye was synthesized as shown in Scheme 1. BODIPY 1 was synthesized according to previously reported similar routine (Figure S1), 50, 51 and the structure was validated by proton nuclear magnetic resonance ( 1H NMR,

Figure

S2).

The

spectrum

of

additional

matrix-assisted

laser

desorption/ionization time-of-light mass spectrometry (MALDI-TOF MS) was shown in Figure S3. Then BODIPY 1 was conjugated with PEG-SS and was successfully synthesized, which was confirmed by 1H NMR (Figure S4). As determined by size-exclusion chromatography (SEC, Figure S5), the weight-average molecular weight (Mw) was 2638 and dispersity (Đ) was 1.08. Amphiphilic PEG-SS-BDP could

be formed into NPs by nanoprecipitation. According to the results of transmission electron microscopy (TEM) in Figure 1a, the diameter of NPs was about 80 nm, which was consistent with results of dynamic light scattering (DLS) in Figure S6a. The time-dependent changes of size and PDI of PEG-SS-BDP NPs in water (Figure 1b), 10% FBS and saline (Figure S6b-c) showed good stability of NPs, which was essential for further bio-application. The reduction-induced breaking of disulfide bonds of PEG-SS-BDP was monitored by DLS. With the addition of GSH, the diameter gradually increased from 89 nm to 350 nm, and the increase of PDI tends to the same tendency (Figure S6c and d).

Scheme 1. Main functions in vitro and in vivo of PEG-SS-BDP NPs.

3.2 Optical properties of NPs. UV-vis absorption and photoluminescence spectra were recorded to monitor the

optical properties. The maximum absorption peak at 730 nm of PEG-SS-BDP NPs in water was red-shifted comparing with that of PEG-SS-BDP in DCM, because of the nanoscale aggregation in aqueous solution (Figure 1c). 16 As shown in Figure 1d, an obvious fluorescence peak at 749 nm of PEG-SS-BDP in DCM could be observed, however, negligible fluorescence intensity of PEG-SS-BDP NPs could be detected because of the aggregation-caused quenching (ACQ).52-54 The inset in Figure 1d visually validated that strong red fluorescence of PEG-SS-BDP in DCM after 700 nm light irradiation whereas the fluorescence of PEG-SS-BDP NPs could hardly be detected. Indocyanine green (ICG, 10 μg/mL) was used to detect the photodynamic effect of PEG-SS-BDP NPs (10 μg/mL) under laser irradiation (685 nm, 12 mW/cm2) for 5 min, however, there was hardly no effect shown in Figure S7.

Figure 1. (a) TEM image and (b) Size and PDI of PEG-SS-BDP NPs in aqueous solution for 2 weeks. Error bars represent the mean ± S.D., n = 3. (c) Normalized

UV-vis absorption spectra and (d) Fluorescence spectra of PEG-SS-BDP (5 μg/mL) in DCM and PEG-SS-BDP NPs (5 μg/mL) in aqueous solution.

3.3 Cellular uptake of NPs. The endocytosis of PEG-SS-BDP NPs was detected by confocal laser scanning microscopy (CLSM). HeLa cells were incubated with PEG-SS-BDP NPs from 0.5 h to 2 h. Red fluorescence could be detected in cell plasma and the fluorescence intensity enhanced with the increase of the incubation time, which confirmed the time-dependent cellular uptake. To demonstrate the GSH-sensitive response, HeLa cells were incubated with 10 mM GSH for 2 h followed by the incubation with PEG-SS-BDP NPs for 0.5 h and 2 h. It could be observed that GSH-pretreated cells showed stronger red fluorescence than cells without GSH pretreatment, especially at 2 h after NPs incubation, illustrating that the reduction-induced breaking of disulfide bonds could accelerate the dissociation of PEG-SS-BDP NPs and turn on the latent fluorescence (Figure 2). The quantitative analysis of CLSM showed that fluorescence intensities were about 63 (0.5 h) and 109 (2 h) in the cells without GSH pretreatment, and 125 (0.5 h) and 225 (2 h) with in cells GSH pretreatment, respectively (Figure S8), which was in accord with the visual images and illustrated the ability of time-dependent cellular uptake of NPs and the function of disulfide bonds.

Figure 2. CLSM images of HeLa cells incubated without (a) and with (b) GSH (10 mM) for 2 h and then with PEG-SS-BDP NPs (25 μg/mL) for 0.5 h and 2 h. Multiple imaging channels are shown in sequence (from left to right): DAPI (blue, cell nuclei), PEG-SS-BDP (red) and merged images. Scale bar, 50 μm. The white arrows show the X axis (Distance) in quantitative analysis in Figure S8.

3.4 Photothermal properties of NPs. As shown in Figure 3a, PEG-SS-BDP NPs (100 μg/mL) were irradiated under 808 nm light (0.5 W/cm2) for 10 min. In order to be applied into photothermal therapy of tumor, the repeatability of photothermal properties is of the same importance as the heating capability. The temperature elevation of each cycle was above 30°C, and no deterioration was observed over 4 cycles, validating the excellent photostability of PEG-SS-BDP NPs (Figure 3a). In Figure 3b, PEG-SS-BDP NPs (25 μg/mL) could increase by 16.4°C and PEG-SS-BDP NPs (100 μg/mL) could increase by 30.9°C after irradiation for 10 min (808 nm, 0.5 W/cm2). With the increase of concentration of PEG-SS-BDP NPs, the heating rate was accelerated, which showed the concentration-dependent photothermal effect. The efficiency of photothermal

conversion was 49.9 % (Figure S9) under the irradiation of 808 nm laser according to the reported methods.22 The intracellular photothermal therapy effect in HeLa (Figure 3c) and human thyroid papillary carcinoma (K1) cell lines (Figure S10a) was monitored by thiazolyl blue tetrazolium bromide (MTT) assays. The results showed the concentration-dependent cytotoxicity of PEG-SS-BDP NPs under irradiation (808 nm, 0.5 W/cm2) while the cell viabilities in the absence of irradiation maintained above 90 % at the same condition. The half-maximal inhibitory concentrations (IC50) in the irradiation group was much lower than that in the dark group which confirmed the practical photothermal therapy effect. The Live/dead staining of HeLa cells was shown in Figure S10b and the dead cells presented red fluorescence, which visually substantiated the PTT effect of PEG-SS-BDP NPs under irradiation. 3.5 Drug loading As an amphiphilic polymer, PEG-SS-BDP could load hydrophobic cargos to form nanoparticles (PTX@PSB NPs). Herein, paclitaxel (PTX) was used as a model drug. TEM images in Figure S11a proved the successful formation of co-assemble nanoparticles. The loading content of PTX was calculated to be 2.8 wt% according to the standard curves. And the loading efficiency was 30.9 wt %. Chemotherapy effect of PTX@PSB NPs was obtained via MTT for 72 h without irradiation, and IC50 was 0.0448 μg/mL for HeLa cells (Figure 3d). The photothermal activity of PTX@PSB NPs was tested for 24 h with or without 808 nm irradiation (0.5 W/cm2) and showed the familiar results with PEG-SS-BDP NPs (Figure S11b), which confirmed that PTX@PSB NPs possess both chemotherapy and photothermal therapy effects. The

chemical toxicity of PTX@PSB NPs was approximately same as PTX in the control group at different concentrations.

Figure 3. (a) Circulatory rise and drop temperature curve of PEG-SS-BDP NPs (100 μg/mL) with irradiation (808 nm, 0.5 W/cm2) for 10 min. (b) Temperature curve of PEG-SS-BDP NPs in different concentrations with irradiation (808 nm, 0.5 W/cm2) for 10 min. (c) MTT results of HeLa cells treated with various concentrations of PEG-SS-BDP NPs with or without 808 nm irradiation (0.5 W/cm2, 7 min). Error bars represent the mean ± S.D., n = 4. (d) Chemical toxicity of HeLa cells treated with PTX@PSB NPs at various concentrations of PTX for 72 h. Error bars represent the mean ± S.D., n = 4.

3.6 NIRF and PA imaging in vivo

PA imaging was applied into living animals. First, we detected the photoacoustic signal of PEG-SS-NPs (1 mg/mL, 200 μL) to affirm the PA imaging effect (Figure S12). The mice bearing cervical tumor were injected intratumorally with PEG-SS-BDP NPs. In Figure 4a, after injection for 12 h, PA signal obviously focused in tumor. On this basis, PEG-SS-BDP NPs were injected intratumorally and intravenously for further NIRF imaging. In Figure S13, NIRF signal gradually enhanced in tumor for and then slightly weakened after 48 h. The mouse was dissected after 72 h and the NIRF imaging of separate organs directly showed the accumulation of PEG-SS-BDP NPs in tumor. Furthermore, mice were injected intravenously with PEG-SS-NPs (1 mg/mL, 200 μL) to verify the NIRF effect. NIRF firstly appeared in the whole body, then increasingly accumulated in tumor and reached to the maximum at the 36th hour (Figure 4b and S14a). With time went by, the intensity of NIRF in tumor gradually receded. The changes of NIRF illustrated that PEG-SS-BDP NPs in blood circulation could migrate to tumor and be metabolized by liver. Meanwhile, NIRF could be observed in liver and other organs (Figure S14b).

Figure 4. (a) PA images of tumor-bearing mouse injected intratumorally with

PEG-SS-BDP NPs (1 mg/mL, 200 μL). (b) NIRF images of tumor-bearing mouse injected intravenously with PEG-SS-BDP NPs (1 mg/mL, 200 μL). The area of red circle is tumor.

3.7 Photothermal treatment Mice bearing U14 cervical tumor were used for cancer treatment. Although intravenous injection is widely used, it is considered that intratumoral injection is also an important way of drug administration which could minimize unwanted biodistribution and have various advantages such as site-specific drug delivery, reduced normal tissue exposure and diminished side effects. 55-58 Herein, intratumoral injection was used for intuitively investigating the drug release and tumor inhibition. Intratumoral injection has been widely used in many works and is confirmed to be safe and efficient.59-61 Temperature at the tumor site in the mice without drug injection could rise from 33.2 to 39.9 °C under 808 nm irradiation (0.5 W/cm2) within 20 min (Figure 5a), while the temperature of mice injected intratumorally with PEG-SS-BDP NPs could reach to the maximum (47.7 °C) at the 5th min. Then the temperature was maintained at around 45 °C for 20 min, which could cause the irreversible damage of cancer cells. Only when the tumor was treated with both PEG-SS-BDP NPs and irradiation, tumor could be inhibited effectively due to fantastic PTT effect. Tumors treated with PEG-SS-BDP NPs or only irradiation could not show any difference from those in the control group (Figure 5b). During the whole experiment, the body weight of mice in all groups kept steady (Figure 5c). Every mouse was taken photos (Figure

S15). 12 days after treatment, tumors were dissected from mice to take photos (Figure 5d) and be weighted (Figure 5e). As expected, tumors in the experimental group are apparently smaller than the other groups, visually confirming the PTT effect of PEG-SS-BDP NPs. The survival rates of mice in all groups are 100%. The results of histological analysis showed that PTT caused extensive necrosis in the tumor tissue of the mice in PTT group, but had no distinct damage to main organs including heart, liver, spleen, lung and kidney (Figure S16), suggesting that PEG-SS-BDP NPs-based PTT therapy was effective and safe. The unchangeableness of weight and scatheless tissue hematoxylin and eosin (H&E) images of the experimental group stated that PTT possessed biosecurity and no severe toxicity.

Figure 5. (a) infrared thermal imaging of mice. (b) The changing curve of real-time tumor volume of mice for 12 days. (c) The changing curve of real-time body weight of mice for 12 days. (d) Visual images of isolated tumors from different groups at the

12th day. (e) Average weight of tumors from different groups. (Error bars represent the mean ± S.D., n = 3; ** 0.001

4. CONCLUSION In summary, we synthesized an amphiphilic NIR BODIPY dye (PEG-SS-BDP) containing disulfide links which was sensitive to endogenous reductive stimuli such as GSH. PEG-SS-BDP could be formed into stable nanoparticles in water via self-assembly and be used for drug delivery. Redox-sensitive disulfide bond could induce the dissociation of PEG-SS-BDP NPs, and facilitate the fluorescence bioimaging. As theranostic nanoparticles, PEG-SS-BDP NPs could be used for photothermal therapy, NIRF and PA imaging. The imaging-associated tumor treatment by photothermal therapy was validated in vivo. BODIPYs for PTT and bioimaging have been reported by some previous work,61-63 but our work is still novel and has some noticeable improvements. First, an amphiphilic redox-sensitive NIR BODIPY was reasonably designed and synthesized by us, which could self-assemble into nanoparticles without surfactants or amphiphilic polymers. While BODIPYs in previous work61-63 were hydrophobic, which could not form the nanoparticles in aqueous media. Furthermore, previous BODIPYs61-63 were not redox-sensitive, which was not suitable for drug loading and controlled release. Our BODIPY nanoparticles were redox-sensitive, which could be used for paclitaxel loading and release. At last, our BODIPY nanoparticles possessed favorable capability of photothermal therapy (PTT), near-infrared fluorescence (NIRF)

imaging and photoacoustic (PA) imaging, while other BODIPYs61-63 cannot possess all the abilities simultaneously. Our work developed a promising BODIPY, which contributes to the efficient, comprehensive and multifunctional imaging and treatment of cancer. We can combine our multifunctional nanoparticles with targeting groups to develop precise theranostic nanoparticles in the future. ASSOCIATED CONTENT Electronic supplementary information. The synthesis routine of PEG-SS-BDP; 1H NMR spectrum and MALDI-TOF MS of BODIPY1; size-exclusion chromatography of PEG-SS-BDP; characterization of PEG-SS-BDP NPs by DLS; MTT for PEG-SS-BDP NPs and PTX@PSB NPs; living/dead staining of HeLa cells; TEM image of PTX@PSB NPs; PA image of PEG-SS-BDP NPs; NIRF image in vivo and average signal of organs; photos of different groups; H&E staining of organs and tumors. Figure S1-S16. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *Zhigang Xie E-mail: [email protected] *Wenhai Lin E-mail: [email protected]

Present Addresses State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China. *Guang Chen E-mail: [email protected] Present Address Department of Thyroid Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, P. R. China. ACKNOWLEDGMENT

This work was supported by the National Natural Science Foundation of China (Project No. 51522307). REFERENCES [1] B. Kim, E. Lee, Y. Kim, S. Park, G. Khang, D. Lee, Dual Acid‐ Responsive Micelle‐ Forming Anticancer Polymers as New Anticancer Therapeutics, Adv. Funct. Mater., 23 (40) (2013) 5091-5097. [2] S.V. Jenkins, D.A. Nedosekin, E.K. Miller, V.P. Zharov, R.P.M. Dings, J. Chen, R.J. Griffin, Galectin-1-based tumour-targeting for gold nanostructure-mediated photothermal therapy, Int. J. Hyperthermia, 34 (1) (2018) 19-29. [3] Y. Lyu, J. Zeng, Y. Jiang, X. Zhen, T. Wang, S. Qiu, X. Lou, M. Gao, K. Pu, Enhancing both biodegradability and efficacy of semiconducting polymer nanoparticles for photoacoustic imaging and photothermal therapy, ACS nano, 12 (2)

(2018) 1801-1810. [4] J. Li, J. Rao, K. Pu, Recent progress on semiconducting polymer nanoparticles for molecular imaging and cancer phototherapy, Biomaterials, 155 (2018) 217-235. [5] X. Huang, I.H. El-Sayed, W. Qian, M.A. El-Sayed, Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods, J. Am. Chem. Soc., 128 (6) (2006) 2115-2120. [6] Z. Zha, X. Yue, Q. Ren, Z. Dai, Uniform polypyrrole nanoparticles with high photothermal conversion efficiency for photothermal ablation of cancer cells, Adv. Mater., 25 (5) (2013) 777-782. [7] C.

Zhang,

X.

Zhao,

H.

Guo,

Synergic

highly

effective

photothermal-chemotherapy with platinum prodrug linked melanin-like nanoparticles, Artificial Cells, Nanomed., Biotechnol., (2018) 1-8. [8] S. Liu, A. Doughty, C. West, Z. Tang, F. Zhou, W.R. Chen, Determination of temperature distribution in tissue for interstitial cancer photothermal therapy, Int. J. Hyperthermia, (2017) 1-8. [9] S. Zhao, X. Zhu, C. Cao, J. Sun, J. Liu, Transferrin modified ruthenium nanoparticles with good biocompatibility for photothermal tumor therapy, J. Colloid Interface Sci., 511 (2018) 325-334. [10] J. Sui, G. Liu, Y. Song, D. Li, X. Dong, J. Wang, W. Yu, Integrating photoluminescence, magnetism and thermal conversion for potential photothermal therapy and dual-modal bioimaging, J. Colloid Interface Sci., 510 (2018) 292-301. [11] W. Lin, Y. Li, W. Zhang, S. Liu, Z. Xie, X. Jing, Near-infrared polymeric

nanoparticles with high content of cyanine for bimodal imaging and photothermal therapy, ACS Appl. Mater. Interfaces, 8 (37) (2016) 24426-24432. [12] X.-M. Zhu, H.-Y. Wan, H. Jia, L. Liu, J. Wang, Porous Pt Nanoparticles with High Near-Infrared Photothermal Conversion Efficiencies for Photothermal Therapy, Adv. Healthcare Mater., 5 (24) (2016) 3165-3172. [13] H. Peng, J. Tang, R. Zheng, G. Guo, A. Dong, Y. Wang, W. Yang, Nuclear-Targeted Multifunctional Magnetic Nanoparticles for Photothermal Therapy, Adv. Healthcare Mater., 6 (7) (2017) 1601289. [14] F. Zhou, D. Xing, Z. Ou, B. Wu, D.E. Resasco, W.R. Chen, Cancer photothermal therapy in the near-infrared region by using single-walled carbon nanotubes, J. Biomed. Opt., 14 (2) (2009) 021009-021009-021007. [15] W. Yin, T. Bao, X. Zhang, Q. Gao, J. Yu, X. Dong, L. Yan, Z. Gu, Y. Zhao, Biodegradable MoO x nanoparticles with efficient near-infrared photothermal and photodynamic synergetic cancer therapy at the second biological window, Nanoscale, (2018). [16] X. Liu, B. Chen, X. Li, L. Zhang, Y. Xu, Z. Liu, Z. Cheng, X. Zhu, Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications, Nanoscale, 7 (39) (2015) 16399-16416. [17] P. Choudhury, K. Das, P.K. Das, l-Phenylalanine-Tethered, Naphthalene Diimide-Based,

Aggregation-Induced,

Langmuir, 33 (18) (2017) 4500-4510.

Green-Emitting

Organic

Nanoparticles,

[18] Q. Tang, W. Xiao, C. Huang, W. Si, J. Shao, W. Huang, P. Chen, Q. Zhang, X. Dong, pH-Triggered and Enhanced Simultaneous Photodynamic and Photothermal Therapy Guided by Photoaccoustic and Photothermal Imaging, Chem. Mater., (2017). [19] K. Miki, A. Enomoto, T. Inoue, T. Nabeshima, S. Saino, S. Shimizu, H. Matsuoka, K. Ohe, Polymeric Self-Assemblies with Boron-Containing Near-Infrared Dye Dimers for Photoacoustic Imaging Probes, Biomacromolecules, 18 (1) (2016) 249-256. [20] Z. Guo, Y. Zou, H. He, J. Rao, S. Ji, X. Cui, H. Ke, Y. Deng, H. Yang, C. Chen, Bifunctional platinated nanoparticles for photoinduced tumor ablation, Adv. Mater., 28 (46) (2016) 10155-10164. [21] W. Lin, Y. Li, W. Zhang, S. Liu, Z. Xie, X. Jing, Near-Infrared Polymeric Nanoparticles with High Content of Cyanine for Bimodal Imaging and Photothermal Therapy, ACS Appl. Mater. Interfaces, 8 (37) (2016) 24426-24432. [22] D. Chen, Q. Tang, J. Zou, X. Yang, W. Huang, Q. Zhang, J. Shao, X. Dong, pH-Responsive

PEG–Doxorubicin-Encapsulated

Aza-BODIPY

Nanotheranostic

Agent for Imaging-Guided Synergistic Cancer Therapy, Adv. Healthcare Mater., 7 (7) (2018) 1701272. [23] L. Huang, Z. Li, Y. Zhao, Y. Zhang, S. Wu, J. Zhao, G. Han, Ultralow-power near infrared lamp light operable targeted organic nanoparticle photodynamic therapy, J. Am. Chem. Soc., 138 (44) (2016) 14586-14591. [24] L. Huang, G. Han, Near Infrared Boron Dipyrromethene Nanoparticles for Optotheranostics, Small Methods, (2018) 1700370.

[25] X. Zhen, J. Zhang, J. Huang, C. Xie, Q. Miao, K. Pu, Macrotheranostic Probe with

Disease‐ Activated

Near‐ Infrared

Fluorescence,

Photoacoustic,

and

Photothermal Signals for Imaging‐ Guided Therapy, Angew. Chem., (2018). [26] Q. Miao, K. Pu, Organic Semiconducting Agents for Deep‐ Tissue Molecular Imaging:

Second

Near‐ Infrared

Fluorescence,

Self‐ Luminescence,

and

Photoacoustics, Adv. Mater., (2018) 1801778. [27] W. Lin, T. Sun, Z. Xie, J. Gu, X. Jing, A dual-responsive nanocapsule via disulfide-induced self-assembly for therapeutic agent delivery, Chem. Sci., 7 (3) (2016) 1846-1852. [28] A. Yuan, J. Wu, X. Tang, L. Zhao, F. Xu, Y. Hu, Application of near‐ infrared dyes for tumor imaging, photothermal, and photodynamic therapies, J. Pharm. Sci., 102 (1) (2013) 6-28. [29] A. Attaluri, R. Ma, Y. Qiu, W. Li, L. Zhu, Nanoparticle distribution and temperature elevations in prostatic tumours in mice during magnetic nanoparticle hyperthermia, Int. J. Hyperthermia, 27 (5) (2011) 491-502. [30] W. Yang, J. Noh, H. Park, S. Gwon, B. Singh, C. Song, D. Lee, Near infrared dye-conjugated oxidative stress amplifying polymer micelles for dual imaging and synergistic anticancer phototherapy, Biomaterials, 154 (2018) 48-59. [31] H. Abrahamse, M.R. Hamblin, New photosensitizers for photodynamic therapy, Biochem. J, 473 (4) (2016) 347-364. [32] G.F. Paciotti, L. Myer, D. Weinreich, D. Goia, N. Pavel, R.E. McLaughlin, L. Tamarkin, Colloidal Gold: A Novel Nanoparticle Vector for Tumor Directed Drug

Delivery, Drug Deliv., 11 (3) (2004) 169-183. [33] P. Parhi, S.K. Sahoo, Trastuzumab guided nanotheranostics: A lipid based multifunctional nanoformulation for targeted drug delivery and imaging in breast cancer therapy, J. Colloid Interface Sci., 451 (2015) 198-211. [34] F. Chen, G. Hableel, E.R. Zhao, J.V. Jokerst, Multifunctional nanomedicine with silica: Role of silica in nanoparticles for theranostic, imaging, and drug monitoring, J. Colloid Interface Sci., 521 (2018) 261-279. [35] L. Huang, Y. Zhao, H. Zhang, K. Huang, J. Yang, G. Han, Expanding Anti‐ Stokes Shifting in Triplet–Triplet Annihilation Upconversion for In Vivo Anticancer Prodrug Activation, Angew. Chem., 129 (46) (2017) 14592-14596. [36] X. Zhen, C. Xie, K. Pu, Temperature‐ Correlated Afterglow of a Semiconducting Polymer Nanococktail for Imaging‐ Guided Photothermal Therapy, Angew. Chem., 130 (15) (2018) 4002-4006. [37] J. Shi, A.R. Votruba, O.C. Farokhzad, R. Langer, Nanotechnology in drug delivery and tissue engineering: from discovery to applications, Nano Lett., 10 (9) (2010) 3223-3230. [38] Y. Zhu, B. Yang, S. Chen, J. Du, Polymer vesicles: Mechanism, preparation, application, and responsive behavior, Prog. Polym. Sci., 64 (2017) 1-22. [39] G. Ulrich, A. Barsella, A. Boeglin, S. Niu, R. Ziessel, BODIPY-Bridged Push–Pull Chromophores for Nonlinear Optical Applications, Chemphyschem, 15 (13) (2014) 2693-2700. [40] W.-H. Chen, C.-X. Yang, W.-X. Qiu, G.-F. Luo, H.-Z. Jia, Q. Lei, X.-Y. Wang,

G. Liu, R.-X. Zhuo, X.-Z. Zhang, Multifunctional Theranostic Nanoplatform for Cancer Combined Therapy Based on Gold Nanorods, Adv. Healthcare Mater., 4 (15) (2015) 2247-2259. [41] J. Zhou, G. Tian, L. Zeng, X. Song, X.-w. Bian, Nanoscaled Metal-Organic Frameworks for Biosensing, Imaging, and Cancer Therapy, Adv. Healthcare Mater., 7 (10) (2018) 1800022. [42] H. Wei, R.-X. Zhuo, X.-Z. Zhang, Design and development of polymeric micelles with cleavable links for intracellular drug delivery, Prog. Polym. Sci., 38 (3) (2013) 503-535. [43] D. Xiao, J.-J. Hu, J.-Y. Zhu, S.-B. Wang, R.-X. Zhuo, X.-Z. Zhang, A redox-responsive mesoporous silica nanoparticle with a therapeutic peptide shell for tumor targeting synergistic therapy, Nanoscale, 8 (37) (2016) 16702-16709. [44] Y. Feng, Q. Yao, J. Li, N. Goswami, J. Xie, J. Yang, Converting ultrafine silver nanoclusters to monodisperse silver sulfide nanoparticles via a reversible phase transfer protocol, Nano Research, 9 (4) (2016) 942-950. [45] X. Du, L. Xiong, S. Dai, Z. Qiao Shi, γ-PGA-Coated Mesoporous Silica Nanoparticles with Covalently Attached Prodrugs for Enhanced Cellular Uptake and Intracellular GSH-Responsive Release, Adv. Healthcare Mater., 4 (5) (2015) 771-781. [46] W. Zhang, W. Lin, X. Zheng, S. He, Z. Xie, Comparing Effects of Redox Sensitivity of Organic Nanoparticles to Photodynamic Activity, Chem. Mater., 29 (4) (2017) 1856-1863. [47] G. Chen, Y. Wang, R. Xie, S. Gong, Tumor-targeted pH/redox dual-sensitive

unimolecular nanoparticles for efficient siRNA delivery, J. Controlled Release, 259 (10) (2017) 105-114. [48] W. Shen, J. Ge, S. He, R. Zhang, C. Zhao, Y. Fan, S. Yu, B. Liu, Q. Zhu, A Self‐ Quenching

System

Based

on

Bis‐ Naphthalimide:

A

Dual

Two‐ Photon‐ Channel GSH Fluorescent Probe, Chemistry–An Asian Journal, 12 (13) (2017) 1532-1537. [49] J. Yu, Y. Cui, H. Xu, Y. Yang, Z. Wang, B. Chen, G. Qian, Confinement of pyridinium hemicyanine dye within an anionic metal-organic framework for two-photon-pumped lasing, Nat. commun., 4 (2013) 2719. [50] X. Wang, P. Wang, S. Xue, X. Zheng, Z. Xie, G. Chen, T. Sun, Nanoparticles based on glycyrrhetinic acid modified porphyrin for photodynamic therapy of cancer, Org. Biomol. Chem., 16 (9) (2018) 1591-1597. [51] L. Quan, W. Lin, T. Sun, Z. Xie, Y. Huang, X. Jing, Green Photocatalysis with Oxygen sensitive BODIPYs under visible light, Catal. Lett., 144 (2) (2014) 308-313. [52] E. Deniz, G.C. Isbasar, O.A. Bozdemir, L.T. Yildirim, A. Siemiarczuk, E.U. Akkaya, Bidirectional switching of near IR emitting boradiazaindacene fluorophores, Org. Lett., 10 (16) (2008) 3401-3403. [53] A.S.

Klymchenko,

Solvatochromic

and

fluorogenic

dyes

as

environment-sensitive probes: design and biological applications, Acc. Chem. Res., 50 (2) (2017) 366-375. [54] Y. Guo, Y. Chen, X. Zhu, Z. Pan, X. Zhang, J. Wang, N. Fu, Self-assembled nanosensor based on squaraine dye for specific recognition and detection of human

serum albumin, Sens. Actuators, B, 255 (2018) 977-985. [55] C.G. Park, C.A. Hartl, D. Schmid, E.M. Carmona, H.-J. Kim, M.S. Goldberg, Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases, Sci. Transl. Med., 10 (433) (2018) 1916. [56] J.R. Upponi, K. Jerajani, D.K. Nagesha, P. Kulkarni, S. Sridhar, C. Ferris, V.P. Torchilin,

Polymeric

micelles:

Theranostic

co-delivery system

for

poorly

water-soluble drugs and contrast agents, Biomaterials, 170 (2018) 26-36. [57] C.-J. Wen, C.T. Sung, I.A. Aljuffali, Y.-J. Huang, J.-Y. Fang, Nanocomposite liposomes containing quantum dots and anticancer drugs for bioimaging and therapeutic delivery: a comparison of cationic, PEGylated and deformable liposomes, Nanotechnology, 24 (32) (2013) 325101. [58] J. Du, Z. Gu, L. Yan, Y. Yong, X. Yi, X. Zhang, J. Liu, R. Wu, C. Ge, C. Chen, Poly (Vinylpyrollidone)‐ and

Selenocysteine‐ Modified

Bi2Se3

Nanoparticles

Enhance Radiotherapy Efficacy in Tumors and Promote Radioprotection in Normal Tissues, Adv. Mater., 29 (34) (2017) 1701268. [59] Y. Lu, Y. Yang, Z. Gu, J. Zhang, H. Song, G. Xiang, C. Yu, Glutathione-depletion mesoporous organosilica nanoparticles as a self-adjuvant and Co-delivery platform for enhanced cancer immunotherapy, Biomaterials, 175 (2018) 82. [60] Q. Zhang, C. Shen, N. Zhao, F.J. Xu, Redox‐ Responsive and Drug‐ Embedded Silica Nanoparticles with Unique Self‐ Destruction Features for Efficient Gene/Drug Codelivery, Adv. Funct. Mater., 27 (10) (2017) 1606229. [61] Y. Liu, N. Song, L. Chen, S. Liu, Z. Xie, Synthesis of a Near-Infrared BODIPY

Dye for Bioimaging and Photothermal Therapy, Chem. Asian J., 13 (8) (2018) 989-995. [62]Y. Gawale, N. Adarsh, S.K. Kalva, J. Joseph, M. Pramanik, D. Ramaiah, N. Sekar, Carbazole-Linked Near-Infrared Aza-BODIPY Dyes as Triplet Sensitizers and Photoacoustic Contrast Agents for Deep-Tissue Imaging, Chem. Eur. J., 23 (27) (2017) 6570. [63] M. Zhao, Y. Xu, M. Xie, L. Zou, Z. Wang, S. Liu, Q. Zhao, Halogenated Aza-BODIPY for Imaging-Guided Synergistic Photodynamic and Photothermal Tumor Therapy, Adv Healthc Mater, 7 (18) (2018) e1800606.

Graphical Abstract