Department of Oral and Maxillofacial-Head Neck Oncology, Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
National Clinical Research Center for Oral Diseases, Shanghai 200011, China.
Theranostics. 2019 May 18;9(11):3293-3307. doi: 10.7150/thno.32867. eCollection 2019.
The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients. However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O) consumption and distorted tumor blood vessels. Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT. Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O sustainably through the Fenton reaction. In contrast to traditional strategies that increase O based on decomposition of limited concentration of hydrogen peroxide (HO), our methodology could maintain the concentration of HO and O through the Fenton reaction. : For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens. Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking. Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both and . : SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment. Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues. More significantly, The over-accumulated intracellular ROS, increased O concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation. : Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
光动力疗法 (PDT) 的非侵入性特性使癌症患者能够保留器官功能。然而，肿瘤微环境 (TME) 中的缺氧会阻碍 PDT 的进行，这是由于细胞内氧气 (O) 消耗高和肿瘤血管扭曲造成的。因此，增加 TME 中的氧气生成将是一种很有前途的方法，可以增强 PDT。在此，我们基于细胞铁死亡的生化特性提出了一个铁死亡促进 PDT 的概念，该概念通过产生活性氧 (ROS) 并通过芬顿反应持续供应 O，显著提高了 PDT 的疗效。与基于有限浓度过氧化氢 (HO) 分解来增加 O 的传统策略不同，我们的方法可以通过芬顿反应维持 HO 和 O 的浓度。为了研究其与铁死亡敏感性的关系，我们通过生物信息学分析和口腔舌鳞状细胞癌 (OTSCC) 标本的免疫组织化学分析来描述溶质载体家族 7 成员 11 (SLC7A11) 的表达。之后，光敏剂氯代乙六嗪 (Ce6) 和铁死亡诱导剂 erastin 通过氢键和 π-π 堆积自组装成一种新型超分子 Ce6-erastin 纳米药物。然后，对获得的 Ce6-erastin 进行了广泛的表征，并评估了其对 OTSCC 的抗肿瘤疗效。结果发现，SLC7A11 在 OTSCC 中表达上调，这是铁死亡介导的 OTSCC 治疗的潜在靶点。Ce6-erastin 纳米粒对正常组织的细胞毒性较低。更重要的是，在照射下，CAL-27 细胞中过度积累的细胞内 ROS、增加的 O 浓度和抑制 SLC7A11 表达导致细胞毒性增强，对异种移植肿瘤小鼠模型的抗肿瘤效果令人满意。我们的铁死亡促进 PDT 方法通过缓解缺氧和促进 ROS 产生显著增强了抗癌作用，为克服癌症治疗中 PDT 与缺氧相关的耐药性提供了一种新方法。
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