Asymmetric small organic molecule-based NIR-II fluorophores for high performance tumor phototheranostics†

Qi Wang‡ ^ab, Xinrui Niu‡ ^a, Linqiang Yang‡ ^c, Jiawei Liu ^a, Jing Wang ^a, Xingpeng Xu ^a, Weihua Tang *^c, Wei Huang ^a and Quli Fan *^a
aState Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, China. E-mail: iamqlfan@njupt.edu.cn
^bState Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
^cSchool of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China. E-mail: whtang@njust.edu.cn

First published on 2nd June 2021

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Introduction

Despite making considerable and significant advances to optimize the therapeutic outcomes, malignant tumors remain a grave threat to human health.¹ Recently, phototheranostics have been manifested as a non-invasive and effective medical technology to offer diverse information about cancer treatments such as real-time identification of tumor location and evaluation of therapeutic outcome, exhibiting huge advantages over conventional tumor therapeutics.² Unfortunately, the developed phototheranostic nanoplatforms are still hindered by multiple limitations: (1) they are generally constructed by integrating various diagnostic and therapeutic components, which results in complicated preparation routes and unstable nanostructures;³ (2) multiple excitation wavelengths are usually needed to realize the functions of imaging and therapy, which may prolong therapy time and produce unjustified side effects to sufferers;⁴ (3) the current phototheranostic systems mainly employ near-infrared I (NIR-I, 650–900 nm) fluorescence imaging.⁵ However, its limited tissue penetration depth and spatial resolution tremendously hamper the diagnostic accuracy;⁶ (4) most photothermal agents or photosensitizers are found to suffer from low photothermal conversion efficiency (PCE) or unsatisfactory reactive oxygen species (ROS) generation, which is harmful to photothermal therapy (PTT) or photodynamic therapy (PDT);⁷ (5) single-mode PTT or PDT shows limited therapeutic efficacy.⁸ Consequently, the exploration of single-component-based phototheranostic nanoplatforms for high performance diagnosis and therapy under single NIR illumination is extremely worthwhile.

It is well known that photons emitted from fluorophores exhibit higher tissue penetration depth, and less tissue scattering and absorption as wavelengths increase.⁹ Near-infrared II (NIR-II, 1000–1700 nm) fluorescence imaging is skillfully devised for deep tissue diagnosis in recent years, which presents tremendous advantages over NIR-I fluorescence imaging, such as high detection depth, ultralow auto-fluorescence, remarkable signal-to-background ratios, and superior image quality.¹⁰ Till date, numerous inorganic nanomaterials¹¹ (e.g., quantum dots and rare earth-doped nanoagents) and organic nanomaterials¹² (e.g., conjugated polymers and small molecules) were constructed as NIR-II fluorophores. However, the clinical translation of inorganic nanomaterials was hampered by their potential toxicity concerns.¹³ Moreover, conjugated polymers also have some defects, although they exhibit good biocompatibility. For instance, the molecular weights and optical properties may differ from batch to batch due to the challenging synthesis and purification processes.¹⁴ In contrast, small organic molecules have well-defined chemical structures and optical properties, excellent biodegradation and biocompatibility, high purity, and outstanding repeatability.¹⁵ Nevertheless, the excitation wavelengths of numerous small molecule-based NIR-II fluorophores were below 808 nm (optimal tissue transparent window in the NIR-I region).¹⁶ Moreover, many small molecules only possess photothermal or photodynamic effects with low PCE value or ROS generation,^7e,17 which hinder their phototheranostic outcome. It was remarkable that the integration of PTT and PDT could effectively promote therapeutic performance by covering respective drawbacks.¹⁸ Moreover, small molecules with asymmetric structures could effectively enhance intramolecular charge transfer,¹⁹ leading to the amplification of photothermal conversion capability,²⁰ which is beneficial for tumor treatments. Moreover, according to the Jablonski diagram, the molecular structures of the organic phototheranostic agents significantly influence their optical performances.²¹

Based on the above-mentioned issues, herein, an asymmetric small organic molecule (DTPT) with proper electron acceptor and donor structures was developed as a proof-of-concept example for high performance phototheranostics (Scheme 1). To assure outstanding water-solubility and biocompatibility, DTPT was encapsulated by Pluronic F127 via one-step nanoprecipitation, obtaining DTPT nanoparticles (NPs). The resultant DTPT NPs possessed strong absorption at 808 nm, excellent NIR-II fluorescence emission, robust photostability, and high ROS and hyperthermia production ability (PCE was as high as 61.6%). The results from in vitro and in vivo assays affirmed that DTPT NPs displayed significant antitumor efficacy under a single 808 nm laser irradiation, profiting from the satisfactory NIR-II fluorescence imaging and PTT/PDT performances. Moreover, inappreciable harm to normal tissues of these NPs was also discovered, further demonstrating the safety and potential application of this small molecule in clinical practice.

Results and discussion

Scheme S1 (ESI†) displays the synthetic route of small molecule DTPT. The structure of DTPT was demonstrated via NMR and MALDI-TOF MS (Fig. S1–S7, ESI†). Water-soluble DTPT NPs were easily acquired via a simple nanoprecipitation method using Pluronic F127 as an encapsulation matrix. The data from the TEM assay revealed that the DTPT NPs possess uniform spherical morphology with a diameter of about 90 nm (Fig. 1a), indicating the possible passive tumor-targeting capability of the NPs based on the enhanced permeability and retention effects. The average hydrodynamic size of DTPT NPs was also studied by DLS (Fig. 1a), which matched well with the TEM results. Besides, DTPT NPs displayed outstanding long-term stability with insignificant size change within 5 weeks (Fig. 1b). UV-Vis-NIR spectroscopy confirmed that DTPT NPs in water exhibit broad absorption over 650–900 nm (Fig. 1c), and the molar absorption coefficient at 808 nm of DTPT NPs was as high as 3.49 × 10⁴ M⁻¹ cm⁻¹ (Fig. S8, ESI†), indicating their excellent 808 nm laser absorbance capability. As shown in Fig. 1d, in contrast with indocyanine green (ICG, an FDA-approved NIR dye), the absorption of DTPT NPs displayed negligible change under continuous 808 nm laser irradiation (60 min), suggesting the superb photostability of DTPT NPs. Moreover, DTPT NPs presented outstanding NIR-II fluorescence emission (a major peak at 1087 nm and a shoulder peak at 1242 nm, Fig. 1c) with an appropriate quantum yield (0.76%, using IR-26 as a standard, Fig. S9, ESI†), which provides a suitable candidate for phototheranostics.

Owing to the gratifying optical absorbance capability, the photothermal performances of DTPT NPs were attentively tested. Fig. 2a shows the photothermal profiles of DTPT NPs with various concentrations. Upon 808 nm laser illumination (1 W cm⁻²), higher resultant temperatures of DTPT NPs were found as the concentrations increased, suggesting an apparent concentration-dependent heating effects. When the concentration was 100 μg mL⁻¹, the temperature of the dispersion solution rose quickly to 46.5 °C in 3 min and reached up to 53.1 °C in 10 min, which was enough for efficaciously and irreversibly ablating the tumor cells. Nevertheless, under identical conditions, the temperature change of pure water is inappreciable, corroborating the outstanding photo-to-thermal conversion ability of DTPT NPs. The infrared thermal images of all solutions are presented in Fig. 2b, which further demonstrated the temperature changes. Then, DTPT NPs (100 μg mL⁻¹) were illuminated by an 808 nm laser with diverse power densities. As shown in Fig. 2c, it was distinctly observed that the temperature rise of the DTPT NP solution was positively correlated with the density of the laser. Photothermal stability, as a crucial parameter for tumor therapy, was next studied to evaluate the performance of DTPT NPs. Fig. 2d shows that no apparent difference of temperature elevation upon 808 nm laser illumination for four on/off cycles, affirming their gratifying photothermal stability. As another important parameter to evaluate the performance of DTPT NPs, the PCE value of DTPT NPs was measured based on one on/off cycle. The PCE value was calculated to be as high as 61.6% (Fig. S10, ESI†), which is more extraordinary than that of numerous small molecule nanoparticles,²² conjugated polymer nanoparticles,²³ and inorganic nanoparticles.²⁴

Next, the photodynamic performances of DTPT NPs were investigated upon 808 nm laser irradiation, in which 1,3-diphenylisobenzofuran (DPBF) and indocyanine green (ICG) were used as the singlet oxygen (¹O₂) probe and comparison standard, respectively. The absorption spectra of DPBF treated with DTPT NPs upon 808 nm irradiation are depicted in Fig. S11 (ESI†). It can be seen that the DPBF absorption declined largely upon increasing the power density, confirming ¹O₂ generation in these NPs. In particular, compared to ICG, DTPT NPs exhibited a larger DPBF degradation rate (∼7.1 times of ICG, Fig. 3a–c). Besides, the intracellular ROS generation of DTPT NPs upon 808 nm irradiation was tested using 2′,7′-dichlorodihydrofluorescein diacetate as a detection probe (Fig. 3d). In DTPT NPs + laser group, bright green fluorescence was found. In the DTPT NPs without the laser group, insignificant fluorescence was found, affirming the outstanding NIR-induced ¹O₂ production of DTPT NPs in cells. All these conclusions displayed that DTPT NPs can be used as a promising nanoplatform for PTT/PDT combination therapy.

Excellent biocompatibility of nanomaterials is an essential prerequisite for biomedical applications. The cell viabilities of NIH-3T3 normal cells after incubation with DTPT NPs were estimated by MTT assays. Fig. 4a affirms that DTPT NPs showed inappreciable cytotoxicity even at a high concentration (200 μg mL⁻¹), displaying their exceedingly good biocompatibility. In vitro therapeutic efficacy of DTPT NPs was further estimated by MTT assays. As shown in Fig. 4b, the HeLa cells cultivated with DTPT NPs in different concentrations retained remarkable survival rates without the 808 nm laser illumination, suggesting no dark toxicity of DTPT NPs to cells. However, in the DTPT NPs with the 808 nm laser illumination group, the survival rates of HeLa cells were reduced as the concentrations of DTPT NPs increased, which was due to the excellent PTT/PDT performances of DTPT NPs. Live and dead cell viability assays were further investigated to visually appraise the therapeutic efficacy, in which live and dead cells are shown in green fluorescence (calcein-AM) and red fluorescence (propidium iodide, PI), respectively. Fig. 4c demonstrates that only green fluorescence was found in the DTPT NP group, further implying no dark toxicity of DTPT NPs to cells. Nevertheless, broad red fluorescence was found upon 808 nm laser illumination, suggesting the outstanding phototoxicity of DTPT NPs. All these data indicate that DTPT NPs possess good biocompatibility, inappreciable dark toxicity, and prominent phototoxicity and can serve as promising phototherapeutic agents in vivo.

Imaging plays an essential role in tumor treatment, which has the ability to confirm the optimal therapeutic time, tumor location, and real-time monitoring of the treatment outcome. Before imaging, the blood metabolism of NPs was first studied, which showed a single-compartment pharmacokinetic model (Fig. S12, ESI†). Then, the NIR-II fluorescence imaging property of DTPT NPs in vitro was investigated. The NIR-II signal values and the brightness of NIR-II images were both markedly raised with the rise of the concentration of DTPT NPs (Fig. 5a). Moreover, the NIR-II signals of DTPT NPs (1 mg mL⁻¹) could still be detected even when covered with 10 mm of a chicken-breast tissue, making DTPT NPs hopeful bioimaging agents with deep tissue penetration (Fig. S13, ESI†). The NIR-II imaging property of DTPT NPs in vivo was studied using a HeLa subcutaneous xenograft tumor mouse model by the tail intravenous injection of NPs. As presented in the in vivo NIR-II images (Fig. 5b), the whole-body vessels are clearly discerned from the surrounding background tissues after injection immediately, which was difficult to achieve using traditional NIR-I fluorescence imaging. In addition, the tumor region exhibited gradually enhanced NIR-II fluorescence signals, indicating the gratifying tumor accumulation and fluorescence lighting abilities of the NPs. It should be noted that the NIR-II signals appeared after maximum 29 h of injection (tumour-to-normal-tissue ratio: 1.86) and decreased gradually afterwards owing to metabolism (Fig. 5c). Therefore, 29 h post-injection was determined as an optimal therapeutic time in vivo. Besides, appreciable NIR-II signals are still observed in the tumor region even after 78 h of injection, suggesting the long retention time and long imaging time of DTPT NPs in vivo. Moreover, the NPs showed a higher accumulation in the tumor, liver, and spleen than in heart, lungs, and kidneys, which is affirmed by the NIR-II fluorescence images and fluorescence semi-quantitation of excised tumor and organs (Fig. 5d and Fig. S14, ESI†). All these discoveries corroborated that DTPT NPs could provide powerful guidance for tumor theranostics.

Encouraged by the excellent in vitro therapeutic efficacy of DTPT NPs, the capability of DTPT NPs to produce hyperthermia in vivo was first tested. After 29 h of tail intravenous injection, the temperatures of the tumor were monitored upon the 808 nm laser illumination. As shown in Fig. 6a and Fig. S15 (ESI†), the change in temperature in the PBS group was inappreciable, while the temperature of the tumor in the DTPT NPs group increased to 55 °C after 2 min laser illumination, providing ample hyperthermia for the destruction of cancer cells. Subsequently, four groups of mice were given different treatments to evaluate the in vivo phototherapeutic effects of DTPT NPs by monitoring the changes in the tumor volume (Fig. 6b–d). Similar to control groups, the DTPT NP injected mice exhibited high tumor growth rates, manifesting inappreciable antitumor effects of DTPT NPs in dark. The tumor growth rates of mice treated with DTPT NPs and 808 nm laser irradiation were inhibited significantly due to the outstanding PTT/PDT effects of DTPT NPs (90.8% tumor inhibition rate). The changes in the tumor weight were also monitored, which also corroborated the outstanding phototherapeutic effects of DTPT NPs (Fig. 6e). Moreover, the fluctuations in the body weights of mice were studied to assess the side effects of DTPT NPs. As presented in Fig. 6f, the same trend in the body weight changes in all groups was found, indicating inappreciable harm of DTPT NPs in vivo.

The biosafety of DTPT NPs was further appraised by hematoxylin and eosin (H&E) staining. As presented in Fig. 7, no abnormalities were found in these major organs. However, astonishing lesions were evidently discovered in these tumors handled with DTPT NPs and illumination (Fig. S16, ESI†), revealing the superb safety towards normal tissues and astounding harm to tumor tissues.

Conclusions

In summary, a novel nanoplatform based on single-component asymmetric small organic molecules was successfully constructed for high performance phototheranostics. Apart from the reported advantages of small molecule-based NPs, such as outstanding water-solubility, superb long-term stability, and preeminent photostability, the developed DTPT NPs possessed strong absorption at 808 nm, excellent NIR-II fluorescence emission, high hyperthermia (PCE was as high as 61.6%), and ROS generation ability. The results from in vitro and in vivo assays affirmed that the versatile DTPT NPs displayed significant antitumor efficacy under a single 808 nm laser irradiation (90.8% tumor inhibition rate), profiting from the satisfactory NIR-II fluorescence imaging and PTT/PDT performances. Moreover, these NPs showed superb safety to normal tissues, further demonstrating the potential application of this nanoagent in clinical practice. This study offers fundamental insights for the construction of small molecule-based nanoplatforms for high performance tumor theranostics.

Experimental section

Materials

F127 was obtained from Shanghai Yare Biotech, Inc. All starting materials used in the synthesis of DTPT were purchased from Sigma-Aldrich. Calcein AM/PI stain kit, NIH-3T3 cells, HeLa cells, and HeLa tumor-bearing mice were purchased from Jiangsu KeyGEN BioTECH Corp., Ltd.

Synthetic procedures

Detailed synthetic route of DTPT is presented in Scheme S1 (ESI†).

Preparation of DTPT NPs

DTPT (1 mg) and F127 (10 mg) were dissolved in THF. Then, the solution was quickly injected into water under sonication. Then, DTPT NPs were obtained after centrifugation.

Evaluation of the photothermal/photodynamic performances of NPs

For photothermal performance, the various concentrations of DTPT NPs were exposed to an 808 nm laser (1 W cm⁻²). Besides, 100 μg mL⁻¹ DTPT NPs was exposed to an 808 nm laser with different power densities. The temperature changes and real-time thermal imaging of DTPT NPs were recorded using an infrared thermal imaging camera. For photodynamic performance, the mixture of ROS probe and DTPT NPs were exposed to an 808 nm laser with different power densities. The absorption of the probe was recorded using a UV-Vis-NIR spectrophotometer.

MTT assay

After 24 h of NIH-3T3 or HeLa cells cultivation in the DMEM medium with 10% FBS, various concentrations of DTPT NPs were co-cultured with the NIH-3T3 or HeLa cells for another 24 or 4 h. Moreover, one group of HeLa cells was treated without laser illumination. Another group was treated with 808 nm laser (1 W cm⁻², 4 min) illumination. After further culture of cells with a fresh culture medium, an MTT assay was carried out. The absorbance was determined with a microplate reader.

In vivo NIR-II imaging

The imaging performance of DTPT NPs was tested using HeLa subcutaneous xenograft tumor mouse model. After injection of NPs (2 mg mL⁻¹, 150 μL), NIR-II images were acquired utilizing an in vivo NIR-II imaging system (E_x = 808 nm).

In vivo cancer treatment

All animal investigations were studied with the permit from the Animal Ethics Committee of Simcere BioTech Corp., Ltd., and performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Jiangsu KeyGEN BioTECH Corp., Ltd (china). Four groups (4 mice each) of mice were given different treatments: (1) PBS (150 μL), (2) PBS (150 μL) and 808 nm laser irradiation (1 W cm⁻², 10 min), (3) DTPT NPs (1 mg mL⁻¹, 150 μL), (4) DTPT NPs (1 mg mL⁻¹, 150 μL) and 808 nm laser (1 W cm⁻², 10 min). After tail intravenous injection, the changes in tumor volume, tumor weight, and mice body weight were monitored to evaluate the in vivo treatment effect of DTPT NPs. H&E staining of major organs and tumor was carried out after treatment using standard techniques for histology studies.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21602112, 21674048), the Macao Young Scholars Program (No. AM2020030), NUPTSF (No. NY220198), the Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University (No. OPSKLB202006).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Synthetic procedures, molar absorption coefficient etc. See DOI: 10.1039/d1qm00472g

‡ These authors contributed equally to this work.

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