In this study, an intelligent pH and ROS dual-responsive drug delivery system based on an apoferritin (AFt) nanocage was prepared. This therapeutic system can specifically self-target 4T1 breast cancer cells by exploiting L-apoferritin receptor SCARA 5, avoiding the nonspecific binding or aggregation of nanoparticles due to the chemical functionalization for targeting. The characteristics of AFt were utilized for the simultaneous delivery of anticancer drug doxorubicin (DOX) and photosensitizer rose bengal (RB). RB exhibited efficient reactive oxygen species (ROS) generation, which can be applied to photodynamic therapy. Meanwhile, the AFt nanocage was prone to undergoing peptide backbone cleavage when oxidized by ROS. Therefore, by combining the intrinsic pH-responsive property of AFt, the dual ROS/pH-responsive system was developed. The time and location of drug release can be controlled by the combination of internal and external stimulus, which avoids the incomplete drug release under single stimulus response. The drug release rate increased significantly (from 26.1% to 92.0%) under low-pH condition (pH 5.0) and laser irradiation. More DOX from AFt entered the nucleus and killed the tumor cells, and the cell inhibition rate was up to ∼83% (DOX concentration: 5 μg/mL) after 48 h incubation. In addition, the biodistribution and the in vivo antitumor efficacy (within 14 d treatment) of the nanosystem were investigated in 4T1 breast cancer BALB/c mice. The results indicated that the system is a promising therapeutic agent involving ROS/pH dual response, self-targeting, and chemo-photodynamic therapy.

中文翻译：

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一种自靶向，双重RO​​S / pH响应的载铁蛋白纳米笼，用于时空控制的药物递送至乳腺癌。

在这项研究中，基于载铁蛋白（AFt）纳米笼的智能pH和ROS双响应药物输送系统被制备。该治疗系统可通过利用L-apererritin受体SCARA 5特异性地自我靶向4T1乳腺癌细胞，避免了由于靶向的化学功能化而导致的纳米颗粒的非特异性结合或聚集。AFt的特征被用于同时递送抗癌药阿霉素（DOX）和光敏剂玫瑰红（RB）。RB表现出有效的活性氧（ROS）生成，可用于光动力疗法。同时，AFt纳米笼在被ROS氧化时易于发生肽主链裂解。因此，通过结合AFt固有的pH响应特性，开发了双重ROS / pH响应系统。药物释放的时间和位置可以通过内部和外部刺激的组合来控制，从而避免了单一刺激反应下药物释放的不完全。在低pH条件（pH 5.0）和激光照射下，药物释放速率显着增加（从26.1％增至92.0％）。温育48小时后，更多来自AFt的DOX进入细胞核并杀死肿瘤细胞，细胞抑制率高达〜83％（DOX浓度：5μg/ mL）。此外，生物分布和 温育48小时后，更多来自AFt的DOX进入细胞核并杀死肿瘤细胞，细胞抑制率高达〜83％（DOX浓度：5μg/ mL）。此外，生物分布和 温育48小时后，更多来自AFt的DOX进入细胞核并杀死肿瘤细胞，细胞抑制率高达〜83％（DOX浓度：5μg/ mL）。此外，生物分布和在4T1乳腺癌BALB / c小鼠中研究了纳米系统的体内抗肿瘤功效（在14 d处理内）。结果表明，该系统是涉及ROS / pH双重反应，自我靶向和化学光动力疗法的有前途的治疗剂。