Nitrogen mustard (NM) is among the earliest drugs used to treat malignant tumors and it kills tumor cells by cross-linking DNA. Unfortunately, because of the short half-life and unfavorable selectivity, NM causes significant damage to normal tissues. As NM can increase the levels of reactive oxygen species (ROS) in tumor cells, a ROS-activated nitrogen mustard prodrug (NM-Pro) was synthesized and mixed with NM at a specific ratio to obtain an "NM-ROS-NM-Pro-NM" positive feedback system, which ultimately achieves a specific lethal effect on hematological neoplasms. The further encapsulation of NM/NM-Pro in liposomes allows the sustained release of the drug and prolongs the residence time in vivo. Here, we prepared stable liposomes with a uniform particle size of 170.6 ± 2.2 nm. The optimal ratio of NM to NM-Pro in this study was 2:1. The active drug NM in the NM/NM-Pro system continuously stimulated ROS production by the cells, which in turn further activated the NM-Pro to continuously generate NM. The positive feedback pathway between the NM and NM-Pro resulted in the specific death of tumor cells. Furthermore, the K562 hematological neoplasm model was utilized to evaluate the therapeutic effect of NM/NM-Pro liposomes in vivo. After encapsulation in liposomes, the targeting of tumor cells was increased approximately two times compared with that of normal cells, and NM/NM-Pro liposomes exhibited reduced toxicity, without an increase in drug activity compared to the NM/NM-Pro combination. The NM/NM-Pro delivery system exerts a positive feedback effect on ROS production in tumor cells and displays good potential for the specific killing of hematoma cells.

中文翻译：

---

在血液肿瘤模型中，通过细胞内ROS反馈机制激活的脂质体氮芥子前药制剂的毒性降低。

氮芥（NM）是用于治疗恶性肿瘤的最早药物之一，它通过交联DNA杀死肿瘤细胞。不幸的是，由于半衰期短和选择性不利，NM对正常组织造成重大损害。由于NM可以增加肿瘤细胞中的活性氧（ROS）的水平，因此合成了ROS活化的氮芥前药（NM-Pro），并以特定比例与NM混合以获得“ NM-ROS-NM-Pro -NM“阳性反馈系统，最终对血液肿瘤产生特定的致死作用。NM / NM-Pro在脂质体中的进一步包封允许药物的持续释放并延长体内停留时间。在这里，我们制备了稳定的脂质体，其均匀粒径为170.6±2.2 nm。在这项研究中，NM与NM-Pro的最佳比例为2：1。NM / NM-Pro系统中的活性药物NM不断刺激细胞产生ROS，从而进一步激活NM-Pro连续产生NM。NM和NM-Pro之间的正反馈途径导致肿瘤细胞特异性死亡。此外，使用K562血液肿瘤模型来评估NM / NM-Pro脂质体在体内的治疗效果。包封在脂质体中后，与正常细胞相比，肿瘤细胞的靶向性增加了约两倍，并且与NM / NM-Pro组合相比，NM / NM-Pro脂质体的毒性降低了，而药物活性却没有增加。NM / NM-Pro递送系统对肿瘤细胞中的ROS产生正反馈作用，并显示出特异性杀伤血肿细胞的良好潜力。