College of Pharmacy, Jinan University, Guangzhou 511443, Guangdong, P. R. China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, P. R. China.
ACS Nano. 2023 Mar 28;17(6):5486-5502. doi: 10.1021/acsnano.2c10830. Epub 2023 Mar 8.
Lung cancer with the highest mortality poses a great threat to human health. Ferroptosis therapy has recently been raised as a promising strategy for lung cancer treatment by boosting the reactive species (ROS) production and lipid peroxidation (LPO) accumulation intracellularly. However, the insufficient intracellular ROS level and the unsatisfactory drug accumulation in lung cancer lesions hamper the efficacy of ferroptosis therapy. Here, an inhalable biomineralized liposome LDM co-loaded with dihydroartemisinin (DHA) and pH-responsive calcium phosphate (CaP) was constructed as a ferroptosis nanoinducer for achieving Ca-burst-centered endoplasmic reticulum (ER) stress enhanced lung cancer ferroptosis therapy. Equipped with excellent nebulization properties, about 6.80-fold higher lung lesions drug accumulation than intravenous injection made the proposed inhalable LDM an ideal nanoplatform for lung cancer treatment. The Fenton-like reaction mediated by DHA with peroxide bridge structure could contribute to intracellular ROS production and induce ferroptosis. Assisted by DHA-mediated sarco-/endoplasmic reticulum calcium ATPase (SERCA) inhibition, the initial Ca burst caused by CaP shell degradation triggered the Ca-mediated intense ER stress and subsequently induced mitochondria dysfunction to further boost ROS accumulation, which strengthens ferroptosis. The second Ca burst occurred as a result of Ca influx through ferroptotic pores on cell membranes, thus sequentially constructing the lethal "Ca burst-ER stress-ferroptosis" cycle. Consequently, the Ca-burst-centered ER stress enhanced ferroptosis process was confirmed as a cell swelling and cell membrane disruption process driven by notable intracellular ROS and LPO accumulation. The proposed LDM showed an encouraging lung retention property and extraordinary antitumor ability in an orthotropic lung tumor murine model. In conclusion, the constructed ferroptosis nanoinducer could be a potential tailored nanoplatform for nebulization-based pulmonary delivery and underscore the application of Ca-burst-centered ER stress enhanced lung cancer ferroptosis therapy.
肺癌的死亡率最高，对人类健康构成了巨大威胁。最近，通过增加细胞内活性氧（ROS）的产生和脂质过氧化（LPO）积累，铁死亡疗法被提出作为治疗肺癌的一种很有前途的策略。然而，细胞内 ROS 水平不足和肺癌病变部位药物积累不理想，限制了铁死亡疗法的疗效。在这里，构建了一种可吸入的生物矿化脂质体 LDM，该脂质体共载有水飞蓟宾（DHA）和 pH 响应性磷酸钙（CaP），作为一种铁死亡纳米诱导剂，以实现以钙爆发为中心的内质网（ER）应激增强的肺癌铁死亡治疗。由于具有优异的雾化性能，与静脉注射相比，肺部病变药物积累增加了约 6.80 倍，使得所提出的可吸入 LDM 成为治疗肺癌的理想纳米平台。具有过氧化物桥结构的 DHA 介导的芬顿样反应有助于细胞内 ROS 的产生并诱导铁死亡。在 DHA 介导的肌浆/内质网钙 ATP 酶（SERCA）抑制作用的辅助下，由 CaP 壳降解引起的初始 Ca 爆发引发 Ca 介导的强烈 ER 应激，随后诱导线粒体功能障碍进一步增加 ROS 积累，从而增强铁死亡。第二次 Ca 爆发是由于细胞膜上铁死亡孔的 Ca 内流引起的，从而依次构建了致命的“Ca 爆发-ER 应激-铁死亡”循环。因此，证实了以 Ca 爆发为中心的 ER 应激增强铁死亡过程是一个由显著的细胞内 ROS 和 LPO 积累驱动的细胞肿胀和细胞膜破坏过程。所提出的 LDM 在一个原位肺肿瘤小鼠模型中表现出令人鼓舞的肺部保留特性和卓越的抗肿瘤能力。总之，构建的铁死亡纳米诱导剂可以作为一种用于雾化给药的潜在定制纳米平台，并强调了以 Ca 爆发为中心的 ER 应激增强肺癌铁死亡治疗的应用。
