Li Peixia, Du Yayin, Qiu Jingru, Li Donghai, Li Guiling, Shan Gang
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong Province, 250012, P. R. China.
Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
Adv Healthc Mater. 2023 Dec;12(31):e2301517. doi: 10.1002/adhm.202301517. Epub 2023 Sep 19.
Photodynamic therapy is a promising cancer therapeutic method that can damage DNA via photoinduced reactive oxygen species production. However, tumor cells can initiate DNA repair pathways to resist oxidative damage. In this study, a nuclear-targeted photosensitizer PARP-PS with a poly (ADP-ribose) polymerase 1 (PARP1) inhibitory effect is developed based on the reported PARP1 inhibitor, rucaparib. As a dual-mode DNA-damaging agent, PARP-PS damages DNA upon photoirradiation and enhances oxidative DNA damage by blocking the DNA repair pathway via PARP1 inhibition and degradation. Both in vitro and in vivo investigations demonstrate that PARP-PS exhibits high antitumor activity with few side effects in breast cancer. In addition, PARP-PS can act as an immunogenic cell death inducer to activate immune responses characterized by the promotion of cytotoxic T lymphocyte activation and tumor infiltration. Therefore, PARP-PS is a potential multimodal antitumor agent with synergistic phototherapeutic, chemotherapeutic, and immunotherapeutic effects.
光动力疗法是一种很有前景的癌症治疗方法，它可以通过光诱导产生活性氧来损伤DNA。然而，肿瘤细胞可以启动DNA修复途径来抵抗氧化损伤。在本研究中，基于已报道的聚（ADP - 核糖）聚合酶1（PARP1）抑制剂鲁卡帕尼，开发了一种具有PARP1抑制作用的核靶向光敏剂PARP - PS。作为一种双模式DNA损伤剂，PARP - PS在光照射下损伤DNA，并通过抑制和降解PARP1来阻断DNA修复途径，从而增强氧化DNA损伤。体外和体内研究均表明，PARP - PS在乳腺癌中表现出高抗肿瘤活性且副作用较少。此外，PARP - PS可作为免疫原性细胞死亡诱导剂，激活以促进细胞毒性T淋巴细胞活化和肿瘤浸润为特征的免疫反应。因此，PARP - PS是一种具有协同光疗、化疗和免疫治疗作用的潜在多模式抗肿瘤药物。
