Leveraging an electron-acceptor engineering strategy to regulate excitation dynamics of dyes for devising ideal phototherapeutic agents in synergistic photodynamic/mild-photothermal tumor therapy

Recently, the team of Academician Xiaojun Peng from Dalian University of Technology, Associate Professor Haidong Li, and the team of Professor Juyoung Yoon from Ewha Womans University, South Korea cooperated to develop a series of near-infrared (NIR) dyes with aggregation-induced emission (AIE) characteristics, based on an electron-acceptor engineering strategy to regulate the excited-state dynamic processes of dyes. By introducing diphenylamine into the xanthene structural unit, due to the increase in freely rotatable single bonds and asymmetric structures, the dyes exhibited enhanced AIE characteristics as well as potential for photodynamic therapy (PDT), photothermal therapy (PTT), and photoacoustic imaging (PAI). Variation in the number of cyano groups within the dyes could regulate their excitation wavelength, PDT efficacy, and PTT capability. Experimental results showed that Hcy-ON displayed high ROS production and heat-generating capacity under 760 nm laser irradiation. Molecular theoretical calculations indicated that Hcy-ON exhibited a significant spin–orbit coupling matrix element (SOCME) value <S₁|SOC|T₃>, with the minimum energy gap between S₁ and T₁ energy levels being 0.678 eV, which is related to its strongest ROS generation capability. In addition, analyses of the singlet–triplet (S–T) energy gap, electron transition mechanism, root-mean-square displacement (RMSD) value, and Huang–Rhys factor confirmed the excellent photothermal performance of Hcy-ON. This strategy provides a new paradigm for constructing multimodal light-driven tumor therapies. This research work was published in CCS Chemistry.

Background:

Cancer has long been a disease that seriously threatens human health, and its diagnosis and treatment have always been research hotspots. Compared with traditional therapies such as chemotherapy, radiotherapy, and surgery, light-driven therapies based on organic dyes (such as PDT) provide a promising strategy for tumor treatment due to their precise spatiotemporal control and low toxicity to normal tissues. At present, PDT mainly relies on type II reactive oxygen species (ROS) to exert its effect. However, its therapeutic efficacy is easily restricted by the hypoxic tumor microenvironment; meanwhile, fluorescence imaging suffers from insufficient light penetration depth, affecting the diagnostic outcome of tumors. For PTT, photothermal agents generate heat upon light excitation to destroy tumor cells, and thus are not limited by tumor hypoxia. The heat generated in PTT can be used for photothermal imaging (PTI) through thermal imaging systems, allowing real-time monitoring of the treatment process. However, conventional PTT may cause nonspecific thermal damage to normal tissues around the treatment area. Adopting a mild photothermal therapy (MPTT) strategy is expected to effectively alleviate the shortcomings of tumor therapy mentioned above. Furthermore, PAI effectively overcomes the drawback of insufficient penetration depth in diagnosis with photosensitizers. In clinical settings, single-mode therapeutic methods are often limited by the above factors (such as hypoxia, insufficient penetration depth, or potential damage). Developing multifunctional dye molecules with both diagnostic and therapeutic modes is an effective way to address these shortcomings. However, because the photophysical processes of PDT and PTT/PAI are mutually competitive, dye molecules often mainly exhibit only one property. Therefore, by optimizing dye structures to regulate molecular energy dissipation pathways, it is expected that dye molecules could simultaneously possess PTT, PTI, PAI, and PDT functionalities.

Highlights:

Based on an electron-acceptor engineering strategy to regulate dye excited-state dynamics, a series of NIR dyes with AIE characteristics were developed (Figure 1). By introducing diphenylamine into the xanthene structural unit, due to the increase in freely rotatable single bonds and asymmetric structures, the dyes showed enhanced AIE properties as well as potential for PDT, PTT, and PAI. The variation in cyano group number allowed regulation of excitation wavelength, PDT efficacy, and PTT ability. Experimental results demonstrated that Hcy-ON exhibited high ROS generation and heat-production capability under 760 nm laser irradiation. Molecular theoretical calculations revealed that Hcy-ON had a significant SOCME value <S1|SOC|T3>, with the smallest gap between S1 and T1 energy levels being 0.678 eV, corresponding to its strongest ROS production capability. Furthermore, analyses of S–T energy gaps, electron transition mechanisms, RMSD values, and Huang–Rhys factors confirmed the excellent photothermal performance of Hcy-ON.

Notably, in in vivo MPTT/PDT combination therapy using Hcy-ON dye, after a single treatment with 760 nm laser irradiation, good prognostic results were obtained. As shown in Figure 2, one hour after intratumoral injection, irradiation was carried out with a 760 nm laser (300 mW/cm², 360 J/cm²). On the second day after treatment, the tumors of the mice showed scabbing and blackening due to ablation. Subsequently, tumors in the control group and the Hcy-ON-only group grew rapidly, while the “Hcy-ON + Light” group exhibited significant tumor suppression; this meant that tumors gradually turned into black scabs and regressed, and largely healed. Moreover, body weight remained stable in all experimental groups, indicating good biocompatibility. The multifunctional dye developed in this study provides a promising solution to overcome the limitations of single-mode diagnostic and therapeutic molecules.

Summary and outlook:

The Hcy-ON dye constructed in this study achieved fine-tuning of molecular energy levels through regulation of cyano group number, and simultaneously exhibited excellent AIE properties, efficient PDT/PTT therapeutic performance, and dual-mode PAI/PTI imaging capability. Significant imaging depth and synergistic therapeutic effects were demonstrated in both cellular and animal models, showing broad application prospects in the field of precise tumor diagnosis and treatment.

This research work was published in CCS Chemistry. The first author of the paper is Yifu Hao, a master’s student at Dalian University of Technology. The corresponding authors are Prof. Juyoung Yoon from Ewha Womans University, Dr. Shuang Zeng (postdoctoral researcher at the State Key Laboratory of Fine Chemicals, Dalian University of Technology / School of Bioengineering), and Associate Professor Haidong Li (Dalian University of Technology). The work was carefully guided by Academician Xiaojun Peng. This research was also supported by the National Natural Science Foundation of China, the Liaoning Provincial Science Foundation, and the Fundamental Research Funds for the Central Universities.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.