Duan Zeyu, Li Lie, Zhan Qiyu, Chen Jian, Li Qiyan, Liu Ruiyuan, Tu Yinuo
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, People's Republic of China.
Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China.
Int J Nanomedicine. 2025 Jan 6;20:125-139. doi: 10.2147/IJN.S494970. eCollection 2025.
Photo-immunotherapy faces challenges from poor immunogenicity and low response rate due to hypoxic microenvironment. This study presents Rh-PTZ, a small organic molecule with a D-π-A structure, that simultaneously amplifies mitochondria-targeted type-I PDT-dependent immune stimulation for the treatment of hypoxic cancer.
The hydrophobic Rh-PTZ was encapsulated into F127 to prepare Rh-PTZ nanoparticles (Rh-PTZ NPs). The type-I ROS generation ability, mitochondrial targeting capacity, and ICD triggering effect mediated by Rh-PTZ NPs under LED light irradiation were investigated. Based on a 4T1 subcutaneous tumor model, the in vivo biological safety assessment, in vivo NIR fluorescent imaging, and the efficacy of PDT were assessed.
Rh-PTZ could efficiently accumulate in the mitochondrial site and induce O and •OH burst in situ under LED light irradiation, thereby causing severe mitochondrial dysfunction. Rh-PTZ can amplify mitochondrial stress-caused immunogenic cell death (ICD) to stimulate the immune response, promote the maturation of sufficient dendritic cells (DCs), enhance the infiltration of immune cells, and alleviate the tumor immunosuppressive microenvironment.
The mitochondria-targeting type-I PDT holds promise to enhance photo-immunotherapy for hypoxia tumor treatment and overcoming the limitations of traditional immunotherapy.
光免疫疗法面临着由于缺氧微环境导致的免疫原性差和低反应率等挑战。本研究提出了一种具有D-π-A结构的有机小分子Rh-PTZ，它能同时增强线粒体靶向的I型光动力疗法（PDT）依赖性免疫刺激，用于治疗缺氧癌症。
将疏水性的Rh-PTZ包裹于F127中制备Rh-PTZ纳米颗粒（Rh-PTZ NPs）。研究了Rh-PTZ NPs在LED光照射下的I型活性氧生成能力、线粒体靶向能力以及引发免疫原性细胞死亡（ICD）的效应。基于4T1皮下肿瘤模型，评估了体内生物安全性、体内近红外荧光成像以及PDT的疗效。
Rh-PTZ能够在线粒体部位有效蓄积，并在LED光照射下原位诱导O₂和•OH爆发，从而导致严重的线粒体功能障碍。Rh-PTZ可以放大线粒体应激引起的免疫原性细胞死亡（ICD）以刺激免疫反应，促进足够数量的树突状细胞（DCs）成熟，增强免疫细胞浸润，并缓解肿瘤免疫抑制微环境。
线粒体靶向的I型PDT有望增强光免疫疗法对缺氧肿瘤的治疗效果，并克服传统免疫疗法的局限性。
