State Key Laboratory of Organic Electronics and Information Displays, Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), School of Materials Science and Engineering, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China.
School of Materials Science and Engineering, Beihang University, Beijing, 100191, China.
Angew Chem Int Ed Engl. 2024 Sep 23;63(39):e202408874. doi: 10.1002/anie.202408874. Epub 2024 Aug 21.
Overcoming tumor apoptosis resistance is a major challenge in enhancing cancer therapy. Pyroptosis, a lytic form of programmed cell death (PCD) involving inflammasomes, Gasdermin family proteins, and cysteine proteases, offers potential in cancer treatment. While photodynamic therapy (PDT) can induce pyroptosis by generating reactive oxygen species (ROS) through the activation of photosensitizers (PSs), many PSs lack specific subcellular targets and are limited to the first near-infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep-penetrating, organelle-targeted pyroptosis-mediated phototherapy is essential for cancer treatment strategies. Here, we synthesized four molecules with varying benzene ring numbers in thiopyrylium structures to preliminarily explore their photodynamic properties. The near-infrared-II (NIR-II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria-targeting abilities, and a large Stokes shift. Through nano-precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type-I ROS) upon 808 nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor-targeting ability via NIR-II fluorescence imaging (NIR-II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs-mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.
克服肿瘤细胞凋亡抵抗是增强癌症治疗效果的主要挑战。细胞程序性死亡（PCD）的一种裂解形式细胞焦亡（pyroptosis）涉及到炎症小体、Gasdermin 家族蛋白和半胱氨酸蛋白酶，为癌症治疗提供了新的可能性。虽然光动力疗法（PDT）可以通过激活光敏剂（PS）产生活性氧（ROS）来诱导细胞焦亡，但许多 PS 缺乏特定的亚细胞靶点，且仅局限于近红外一区，这可能会降低治疗效果。因此，开发有效的、深穿透的、细胞器靶向的细胞焦亡介导的光疗对于癌症治疗策略至关重要。在这里，我们合成了四种具有不同苯环数的噻咯并吡喃结构的分子，初步探索了它们的光动力性质。近红外二区 PS Z1 具有更高的苯环数，表现出更好的 ROS 生成和线粒体靶向能力，以及较大的斯托克斯位移。通过纳米沉淀法，Z1 纳米颗粒（NPs）在 808nm 激光照射下也能产生高效的 ROS（特别是 I 型 ROS），导致线粒体功能障碍和细胞焦亡与细胞凋亡的联合作用。此外，它们通过近红外二区荧光成像（NIR-II FI）和光声成像（PAI）显示出出色的肿瘤靶向能力。此外，Z1 NPs 介导的光疗能够有效抑制肿瘤生长，且副作用极小。我们的研究结果为癌症治疗提供了一种有前途的策略，值得进一步在 PDT 中进行临床前研究。
