Li Zipeng, Liu Wenkai, Ma Wanying, Zhang Changyu, Fan Jiangli, Peng Xiaojun
State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology Dalian 116024 China
Ningbo Institute of Dalian University of Technology Ningbo 315016 China.
Chem Sci. 2025 Jun 20. doi: 10.1039/d5sc02476e.
Photodynamic therapy (PDT) has attracted considerable interest in recent years as an effective and promising approach for tumor treatment. In particular, nuclear-targeted type I photosensitizers (PSs) can directly damage the nuclear DNA of tumor cells, thereby significantly enhancing the therapeutic efficacy of PDT. However, nuclear DNA-targeted PSs are rarely reported owing to the lack of clear design principles. Here, we developed a novel DNA-targeted photosensitizer (Se-PC) for highly efficient tumor PDT. After incubation with CT DNA, the fluorescence of Se-PC was dramatically enhanced, indicating its great affinity with DNA. Additionally, Se-PC exhibited strong superoxide radical (O˙) generation ability under light irradiation. Due to the interaction between DNA and Se-PC, the generated O˙ directly induced structural damage of DNA, ultimately leading to cell death. experiments showed that Se-PC effectively localized in the nucleus and achieved excellent killing performance against tumor cells. Benefiting from type-I characteristics, cell proliferation was also remarkably inhibited by the combination of Se-PC and excitation light even under severe hypoxic conditions (2% O). Furthermore, studies demonstrated that Se-PC exhibited notable efficacy in the photoablation of solid tumors, endowing Se-PC with great potential for advancing clinical translation of tumor PDT.
近年来，光动力疗法（PDT）作为一种有效且有前景的肿瘤治疗方法引起了广泛关注。特别是，核靶向I型光敏剂（PSs）可直接损伤肿瘤细胞的核DNA，从而显著提高PDT的治疗效果。然而，由于缺乏明确的设计原则，核DNA靶向PSs的报道很少。在此，我们开发了一种新型的用于高效肿瘤PDT的DNA靶向光敏剂（Se-PC）。与CT DNA孵育后，Se-PC的荧光显著增强，表明其与DNA具有很强的亲和力。此外，Se-PC在光照下表现出很强的超氧自由基（O˙）生成能力。由于DNA与Se-PC之间的相互作用，生成的O˙直接诱导DNA的结构损伤，最终导致细胞死亡。实验表明，Se-PC有效地定位于细胞核，并对肿瘤细胞具有优异的杀伤性能。得益于I型特性，即使在严重缺氧条件（2% O）下，Se-PC与激发光的组合也能显著抑制细胞增殖。此外，研究表明Se-PC在实体瘤的光消融中表现出显著疗效，这赋予了Se-PC在推进肿瘤PDT临床转化方面的巨大潜力。
