Li Jingyao, Yi Huixi, Fu Yuanyuan, Zhuang Jiani, Zhan Zhixiong, Guo Liyou, Zheng Ji, Yu Xiyong, Zhang Dong-Yang
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China; State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing 400042, China.
J Colloid Interface Sci. 2025 Feb 15;680(Pt A):9-24. doi: 10.1016/j.jcis.2024.10.156. Epub 2024 Oct 28.
Hypoxia, which is a common characteristic of most solid tumors, not only contributes to the immunosuppressive nature of the tumor microenvironment (TME) but also reduces the efficacy of many oxygen-depleting therapies, including photodynamic therapy (PDT). In this study, we developed acidity-responsive biodegradable iridium-coordinated (IPC) nanodrugs consisting of iridium ions, the photosensitizer chlorin e6 (Ce6), and polyvinylpyrrolidone to potentiate the effects of PDT and immunotherapy by modulating the TME. IPC nanodrugs that accumulate at high levels in tumors catalyze excess hydrogen peroxide to produce oxygen while depleting glutathione levels within cancer cells; thus, the released Ce6 is more efficient at producing reactive oxygen species (ROS) in response to laser irradiation. In addition, IPC nanodrugs alleviate tumor hypoxia, induce more immunogenic cell death by amplifying PDT responses, and synergistically inhibit tumor growth by initiating robust antitumor immunity and reversing the immunosuppressive nature of the TME. As a result, IPC nanodrugs exert pronounced combined therapeutic effects in vitro and in vivo, without obvious toxic effects due to acidity-responsive degradation. These iridium-coordinated nanodrugs have the potential to modulate the TME, amplify the effects of PDT, and substantially inhibit tumors, and they are expected to provide novel ideas for combination therapy of hypoxic cancer.
缺氧是大多数实体瘤的共同特征，它不仅导致肿瘤微环境（TME）的免疫抑制特性，还会降低包括光动力疗法（PDT）在内的许多耗氧疗法的疗效。在本研究中，我们开发了一种酸度响应性可生物降解的铱配位（IPC）纳米药物，其由铱离子、光敏剂二氢卟吩e6（Ce6）和聚乙烯吡咯烷酮组成，通过调节TME来增强PDT和免疫疗法的效果。在肿瘤中高水平积累的IPC纳米药物催化过量的过氧化氢产生氧气，同时降低癌细胞内的谷胱甘肽水平；因此，释放出的Ce6在响应激光照射时更有效地产生活性氧（ROS）。此外，IPC纳米药物可缓解肿瘤缺氧，通过放大PDT反应诱导更多免疫原性细胞死亡，并通过启动强大的抗肿瘤免疫和逆转TME的免疫抑制特性来协同抑制肿瘤生长。结果，IPC纳米药物在体外和体内均发挥出显著的联合治疗效果，且由于酸度响应性降解而无明显毒性作用。这些铱配位纳米药物具有调节TME、放大PDT效果和显著抑制肿瘤的潜力，有望为缺氧癌症的联合治疗提供新思路。
