Roshdy Eslam, Taniguchi Haruto, Nakamura Yoki, Takahashi Haruko, Kikuchi Yutaka, Celik Ismail, Mohammed Elsayed S I, Ishihara Yasuhiro, Morioka Norimitsu, Abe Manabu
Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Higashi-Hiroshima City, Hiroshima 739-8526, Japan.
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
J Med Chem. 2025 Feb 27;68(4):4561-4581. doi: 10.1021/acs.jmedchem.4c02606. Epub 2025 Feb 17.
Resiquimod, an imidazoquinoline scaffold, exhibits potent immunotherapeutic activity but is associated with off-target effects, limiting its clinical utility. To address this limitation, we developed a novel BODIPY-caged resiquimod that is responsive to red light, combining photocaging and photodynamic therapy functionalities. Molecular docking studies guided identification of the optimal caging site for resiquimod, effectively masking its immune activity. BODIPY-caged resiquimod remained inactive under dark conditions, effectively masking resiquimod's immunostimulatory effects. However, red light irradiation precisely uncaged resiquimod, inducing robust immune activation, even in the presence of -acetyl cysteine as an antioxidant. Notably, the attachment of resiquimod to BODIPY reduced the dark toxicity typically associated with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control over cytotoxicity, significantly enhancing cell death only upon irradiation. This dual-function therapeutic approach highlights a "win-win" strategy: precise, red-light-mediated control of immune activation and photodynamic efficacy with reduced collateral toxicity.
瑞喹莫德是一种咪唑喹啉骨架化合物，具有强大的免疫治疗活性，但存在脱靶效应，限制了其临床应用。为解决这一局限性，我们开发了一种新型的硼二吡咯（BODIPY）笼蔽瑞喹莫德，它对红光有响应，兼具光笼蔽和光动力治疗功能。分子对接研究指导确定了瑞喹莫德的最佳笼蔽位点，有效掩盖了其免疫活性。BODIPY笼蔽的瑞喹莫德在黑暗条件下保持无活性，有效掩盖了瑞喹莫德的免疫刺激作用。然而，红光照射能精确地解开瑞喹莫德的笼蔽，即使在存在抗氧化剂乙酰半胱氨酸的情况下也能诱导强烈的免疫激活。值得注意的是，将瑞喹莫德连接到BODIPY上降低了通常与作为光敏剂的BODIPY相关的暗毒性。在HeLa和A549细胞的三维球体模型中，BODIPY笼蔽的瑞喹莫德表现出对细胞毒性的时空控制，仅在照射时显著增强细胞死亡。这种双功能治疗方法突出了一种“双赢”策略：通过红光精确介导免疫激活和光动力疗效，同时降低附带毒性。
