Structural optimization of organic fluorophores for highly efficient photothermal therapy

Abstract

Developing highly efficient organic photothermal agents is desirable and imperative because of the great potential of photothermal therapy in tumor treatment. In this work, three boron dipyrromethene (BDP) molecules (Ph-BDP, Na-BDP and Py-BDP) with different conjugate areas were rationally designed and synthesized to study the effects of molecular structures on photoproperties. With the increase of conjugate areas, the absorption and emission wavelengths of BDP molecules were red-shifted, and the radiative transitions were weakened along with the improvement of non-radiative transitions and enhancement of intersystem crossing (ISC). After formation of BDP nanoparticles, the radiative transitions and ISC were weakened. Importantly, Py-BDP nanoparticles with the largest conjugate area had highest photothermal conversion efficiency (η = 42%) among these BDP nanoparticles, and indicated the best tumor treatment effect in vitro and in vivo. This work provides a systematic strategy for exploiting efficient photothermal agents.

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Introduction

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) has received wide attention in tumor treatment due to its non-invasiveness, slight side effects, and weak drug resistance.^1–7 PDT usually induces apoptosis or necrosis of cancer cells by producing singlet oxygen (¹O₂) in the presence of oxygen or free radicals via photochemical reactions in cells.^8–12 Therefore, PDT is susceptible to the tumor microenvironment (TME).^13–19 In contrast, PTT relies on photothermal agents (PTAs) to cause local overheating under irradiation to kill tumor cells, which is less dependent on the TME.^20–23 Recently, great progress has been made in the combination of PTT with other therapies.^24–27 In addition, infrared thermal imaging could be used to monitor temperature and prevent damage to normal tissues caused by overtreatment during the process of PTT.²⁸

Organic nanomaterials have attracted widespread attention due to their good biocompatibility and potential biodegradability.²⁹ For the organic fluorophore, electron transitions in the excited states mainly in three ways: radiative transitions, non-radiative transitions, and intersystem crossing (ISC).^30–32 To improve the photothermal conversion efficiency (PCE) of PTAs, process of non-radiative transitions must be increased.^33–35 Liu and Pu et al. improved the PCE of dye molecules by preparing conjugated polymers nanoparticles.^36–42 Peng and Yan et al. adjusted the assembly methods to increase the PCE of dyes.^43,44 Although advances have been made in developing effective PTAs, there is a strong desire for a simple and effective method to maximize the photothermal activity of PTAs.⁴⁵

Relative to porphyrin and cyanine, boron dipyrromethene (BDP) possesses various structures, high molar absorbance coefficient and robust photostability.^46–50 It is straightforward to extend the absorption wavelength and improve the phototherapy performance of BDP derivatives by conjugating a class of phenylethylene groups at 1, 3, 5 and/or 7 positions of the BDP backbones (Scheme 1a).^51,52 Relatively, it is easier to introduce groups at 3 and 5 positions due to the less steric effect.^53–55

Scheme 1 (a) The structure of BDP backbone and the structures of Ph-BDP, Na-BDP and Py-BDP. (b) Schematic illustration of the properties of Py-BDP and Py-BDP NPs, as well as the photothermal effects of Py-BDP NPs toward cancer cells.

Herein, to study the effect of conjugate areas on the photoproperties of BDP, phenyl, naphthyl and pyrenyl were introduced to BDP and form Ph-BDP, Na-BDP and Py-BDP, respectively (Scheme 1a). Compared to Ph-BDP and Na-BDP, Py-BDP generated the maximum singlet oxygen upon irradiation at the same condition. And nanoparticle (NP) formulations could effectively suppress emission and ISC of BDP molecules, and maximize the non-radiative relaxation (Scheme 1b). The Py-BDP NPs showed a high PCE and excellent tumor suppressing effect.

Results and discussion

Synthesis and characterization

To synthesize BDP molecules with different conjugate areas, phenyl, naphthyl and pyrenyl were introduced at 3 and 5 positions of BDP (Scheme 1a), and the obtained molecules were named Ph-BDP, Na-BDP and Py-BDP respectively (Scheme 1b). Their chemical structures and molecular weights were proved by ¹H nuclear magnetic resonance (NMR) spectra and MALDI-TOF mass spectrometry (MS) analysis (Fig. S1–S3, ESI†). The absorption and emission spectra of three BDP molecules at the same molar concentration are shown in Fig. 1. The absorption maxima of Ph-BDP, Na-BDP and Py-BDP are at 623, 638 and 692 nm with molar extinction coefficients of 1.074 × 10⁵, 8.24 × 10⁴ and 9.12 × 10⁴ M⁻¹ cm⁻¹, respectively. The emission maxima of three BDP molecules are at 637, 664 and 725 nm, respectively. The red-shifted absorption and emission peaks are expected after increasing the conjugate areas,⁵⁶ which are further explained by the density functional theory (DFT) calculation.

Fig. 1 The (a) absorption and (b) emission spectra of Ph-BDP, Na-BDP and Py-BDP in N,N-dimethylformamide (10 μM). The excitation wavelengths were 620, 640 and 700 nm.

The gap of highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) (HLG) determines the optical and electronic properties of organic molecules.⁵⁷ Electron distributions of Ph-BDP, Na-BDP and Py-BDP are shown in Fig. 2a, increasing the conjugation degree of organic molecules could reduce HLG to some extent. The calculated energy gaps of three BDP molecules were 2.24, 2.19 and 1.99 eV, respectively. Among these three BDPs, Py-BDP showed the maximum redshifts in absorption and emission spectra, and the electrons were more easily excited. As shown in Fig. 2b, the energy of the excited states (Sn and Tn) gradually decreased and moved to the lowest excited states (S₁ and T₁) with the increase of conjugate areas. The smaller differences between different energy levels are more favorable for the ISC process to promote the generation of ¹O₂,⁵⁸ that is, Py-BDP generates ¹O₂ more easily. When 1,3-diphenylisobenzofuran (DPBF) was used to detect the abilities of generating ¹O₂, it was found that Py-BDP reduced the absorbance of DPBF more significant than Ph-BDP and Na-BDP under the same conditions (Fig. 2c). This result is consistent with the theoretical calculations.

Fig. 2 (a) HOMO and LUMO of the geometry structures and (b) excited singlet and triplet energy levels of Ph-BDP, Na-BDP and Py-BDP. Optimized with Gaussian 09/B3LYP/6-31G*. (c) Absorption spectra of DPBF in the presence of three BDP molecules under red LED light (27 mW cm⁻²) irradiation for different time.

Preparation and characterization of BDP NPs

Subsequently, BDP molecules could form NPs through nanoprecipitation method in the absence of surfactants, and they were named Ph-BDP NPs, Na-BDP NPs and Py-BDP NPs, respectively. The absorption maxima of three BDP NPs are at 643, 661 and 728 nm (Fig. 3a). Moreover, NPs show broadened absorption spectra with redshifts of about 20 nm as compared to dissolved BDP molecules because of the aggregation effect. At the same time, the fluorescence of NPs is poor because of the aggregation-caused quenching (ACQ) (Fig. S4, ESI†), which is shown under illumination of ultraviolet (UV) lamp (Fig. 3b). Moreover, three BDP NPs showed similar zeta potential of about −8 eV (Fig. 3c), and regular spherical shapes with sizes of about 200 nm as evidenced by transmission electron microscopy (TEM) images and dynamic light scattering (DLS) measurements (Fig. 3d–f). In addition, no obvious size changes were observed for BDP NPs in different conditions (Fig. S5, ESI†), indicating that NPs had excellent colloidal stability. These data demonstrate that there is no significant difference in the morphology, particle size, zeta potential and stability of three BDP NPs.

Fig. 3 (a) The absorption spectra of Ph-BDP NPs, Na-BDP NPs and Py-BDP NPs in water. (b) Photograph of BDP and BDP NPs (I: Ph-BDP, II: Na-BDP, III: Py-BDP) under the UV lamp. (c) Zeta potential of different BDP NPs. The results are represented as mean ± SD (n = 3). Error bars represent standard deviations of three independent experiments. Size distribution of (d) Ph-BDP NPs, (e) Na-BDP NPs and (f) Py-BDP NPs measured by DLS and TEM images (inset).

Photothermal effects

9,10-Anthracenediyl-bi(methylene)-dimalonic acid (ABDA) was used to detect the ability of three BDP NPs to produce ¹O₂ (Fig. S6, ESI†). As expected, the ISC of BDP was quenched after the NPs were formed. The low quantum yield of ¹O₂ and fluorescence intensity is conducive to the photothermal effect.¹⁹ Subsequently, the photothermal activity was investigated. Under the same illumination conditions (685 nm laser, 0.55 W cm⁻² for 5 min), the temperature of Ph-BDP NPs (25 μM), Na-BDP NPs (25 μM) and Py-BDP NPs (10 μM) were raised 26.7, 26.9 and 30.2 °C respectively (Fig. 4a–c). The PCE (η) of Ph-BDP NPs, Na-BDP NPs and Py-BDP NPs were 22%, 28% and 42%, respectively (Fig. S7, ESI†). The PCE of Py-BDP NPs is higher than some of the reported organic agents.^32,42 Further research showed that the photothermal capability of Py-BDP NPs was concentration and power-intensity dependent (Fig. 4d and e). During the five cycles of heating and cooling, the increased temperature basically did not change, indicating that the Py-BDP NPs had high irradiation stability (Fig. 4f).

Fig. 4 (a–c) Photothermal effect of three BDP NPs under irradiation of a 685 nm laser (0.55 W cm⁻²), and the laser was turned off after irradiation for 5 min. (d) Photothermal effect of Py-BDP NPs at various concentrations under irradiation of a 685 nm laser (0.55 W cm⁻²). (e) Photothermal effect of Py-BDP NPs (10 μM) with various laser power densities. (f) Photothermal effect of Py-BDP NPs upon five cycles of heating and cooling.

Cell uptake and cytotoxicity

To illustrate the cellular uptake of three BDP NPs, we assessed their internalization by human cervical carcinoma (HeLa) cells. It was observed by confocal laser scanning microscope (CLSM) that three BDP NPs could be efficiently internalized by cells (Fig. S8, ESI†). Subsequently, in vitro biocompatibility and phototoxicity of three BDP NPs were tested by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Three BDP NPs displayed a concentration-dependent cytotoxicity under laser irradiation (Fig. 5a–c). And the cell activity of cells in the absence of irradiation was all above 90%, indicating the good cell compatibility, of BDP NPs. It is worth noting that Py-BDP NPs could inhibit cell growth at a lower concentration (10 μM) than other two NPs (25 μM) due to the higher PCE. Furthermore, the experimental results in mouse breast carcinoma (4T1) cells (Fig. 5d–f) are similar to those in HeLa cells. In practical applications, it is not advisable to use large doses of drugs to achieve tumor ablation, thus Py-BDP NPs are more likely to meet the requirements.

Fig. 5 Cell viability of three BDP NPs against (a–c) HeLa and (d–f) 4T1 cells without (dark) or with (light) 685 nm laser irradiation (0.55 W cm⁻², 5 min). The results are represented as mean ± SD (n = 3). Error bars represent standard deviations of three independent experiments. ***p < 0.001.

PTT effects of NPs

On the basis of above results, the PTT effects of three BDP NPs in vivo were studied. Mouse cervical carcinoma (U14) cells were subcutaneously injected into the legs of Kunming mice. After 6 days, the tumor-bearing mice were randomly divided into four groups with different treatments: PBS + light irradiation (L), Ph-BDP NPs + L, Na-BDP NPs + L and Py-BDP NPs + L. After intratumoral injection of NPs for 1 h, the tumor sites were treated with 685 nm laser (0.55 W cm⁻², 10 min). In the process of illumination, the temperatures of tumor sites were monitored by near infrared thermal camera. The temperature at tumors in Py-BDP NPs + L increased to about 54 °C after illumination for 10 min (Fig. 6a and b). However, there was little difference in temperature at tumor of mice treated by Ph-BDP NPs + L and Na-BDP NPs + L, probably due to the similar PCEs of these two NPs. The tumor volumes of mice were recorded every other day. In Fig. 6c, the tumor volumes of mice treated by Ph-BDP NPs + L, Na-BDP NPs + L and Py-BDP NPs + L were smaller than those by PBS + L, demonstrating the effective inhibition of tumor growth by BDP NPs under laser irradiation. And the growth of tumors in the Py-BDP NPs + L was the most dramatically inhibited, which was also evidenced by the weights and picture of isolated tumors (Fig. 6d and e). In the process of treatment, the body weights of mice in each group displayed a rising trend (Fig. 6f). The above experimental results further verify that Py-BDP NPs possess the best ability of PTT.

Fig. 6 (a) Infrared thermal images of tumors injected with PBS or three BDP NPs, and then exposed to a 685 nm laser (0.55 W cm⁻², 10 min). (b) Temperature changes of tumors in different groups. (c) Tumor volume changes of mice in different groups during treatment. (d) Tumor weights and (e) the tumor picture in the different groups. (f) Body weights of the mice during the therapy period. The results are represented as mean ± SD (n = 4). Error bars represent standard deviations of four independent experiments. *p < 0.05; **p < 0.01.

The antitumor effect of Py-BDP NPs was further investigated through the systemic administration. Py-BDP@F127 NPs were prepared by encapsulating Py-BDP into Pluronic F127 micelles (Fig. 7a). Since Py-BDP showed an emission maximum at 725 nm, the NIRF imaging performance of Py-BDP@F127 NPs was studied in living mice. After Py-BDP@F127 NPs were injected into tail veins of tumor bearing mice, the whole bodies of mice were imaged at different time. As shown in Fig. S9a (ESI†), the fluorescence intensity of tumor sites increased gradually, indicating that Py-BDP@F127 NPs could accumulate in tumors. Semiquantitative analysis of the fluorescence intensity of the tumor sites showed that the NPs reached a maximal accumulation in the tumors at 9 h post injection (Fig. S9b, ESI†).

Fig. 7 (a) Schematic illustration of the preparation of Py-BDP@F127 NPs and their applications in PTT of tumors in vivo. (b) Temperature changes of tumors in different groups. (c) Tumor volume changes of mice in each group during treatment. (d) Tumor weights of mice after various treatments. (e) Tumor images after different treatments. I: PBS, II: PBS + L, III: NPs, IV: NPs + L. (f) H&E staining of tumor tissues. (g) Body weights of the mice during the therapy period. The results are represented as mean ± SD (n = 4). Error bars represent standard deviations of four independent experiments. ***p < 0.001.

The therapeutic effect of Py-BDP@F127 NPs was studied after intravenous injection into U14 tumor bearing Kunming mice. The mice were randomly divided into four groups, named PBS, PBS + L, Py-BDP@F127 NPs and Py-BDP@F127 NPs + L respectively. The mice in PBS + L and Py-BDP@F127 NPs + L were intravenously injected with PBS and Py-BDP@F127 NPs, and after 9 h, the tumor sites were irradiated with 685 nm laser (0.4 W cm⁻², 10 min). The temperature changes of tumors monitored by infrared thermal camera clearly showed that the temperature of tumors in NPs + L was significantly higher than that in PBS + L (Fig. S10, ESI†). The tumor growth of mice in PBS, PBS + L and NPs could not be inhibited, and the tumor volumes increased with an average of 18–20 times (Fig. 7c). However, the tumor growth in Py-BDP@F127 NPs + L was markedly inhibited, which was further confirmed by the weights (Fig. 7d) and picture of isolated tumors (Fig. 7e) after treatment. From hematoxylin and eosin (H&E) staining images of tumor regions (Fig. 7f), severe damage to tumor cells could be detected in NPs + L, while no distinct cell destruction could be observed for the PBS + L. These results prove that the photothermal properties of Py-BDP@F127 NPs could effectively inhibit the tumor growth.

Moreover, Py-BDP@F127 NPs also showed superior physiological safety in vivo. In the process of treatment, the body weights of mice in each group displayed a rising trend, showing that the systematic toxicity of all treatment methods was very low (Fig. 7g). After the treatment, H&E staining was performed on isolated organs (heart, liver, spleen, lung and kidney) of mice.^59,60 As shown in Fig. S11 (ESI†), no obvious damage was found in different organs. This further indicated that Py-BDP@F127 NPs had good biocompatibility at current dose.

Conclusions

In summary, three BDP fluorophores (Ph-BDP, Na-BDP and Py-BDP) with different conjugate areas were synthesized. The results of DFT simulation show that the energy gap decreases with the increase of conjugate area, and Py-BDP with the largest conjugate area possesses better phototherapy performance. The formed BDP NPs could prevent the production of ROS and quench the fluorescence of BDP molecules, thus improving the photothermal activity. Finally, the photothermal property of Py-BDP NPs was validated by the potent phototoxicity and effective tumor treatment. This work highlights the potential of precise design of photoactive organic nanomaterials with tunable photothermal activity.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The work was supported by the National Natural Science Foundation of China (project no. 51973214).

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Footnote

† Electronic supplementary information (ESI) available: Materials, characterizations and experiments. See DOI: 10.1039/d0qm00624f

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