Reduced Toxicity of Liposomal Nitrogen Mustard Prodrug Formulation Activated by an Intracellular ROS Feedback Mechanism in Hematological Neoplasm Models.
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.
['Lin|Mengting|M|', 'Guo|Wangwei|W|', 'Zhang|Zhentao|Z|', 'Zhou|Yi|Y|', 'Chen|Jiejian|J|', 'Wang|Tiantian|T|', 'Zhong|Xincheng|X|', 'Lu|Yiying|Y|', 'Yang|Qiyao|Q|', 'Wei|Qichun|Q|', 'Han|Min|M|0000-0001-9373-8466', 'Xu|Donghang|D|', 'Gao|Jianqing|J|0000-0003-1052-7060']
D000818:Animals D018906:Antineoplastic Agents, Alkylating D002470:Cell Survival D004195:Disease Models, Animal D004339:Drug Compounding D016503:Drug Delivery Systems D065546:Drug Liberation D025461:Feedback, Physiological D005260:Female D019337:Hematologic Neoplasms D006801:Humans D020014:K562 Cells D008081:Liposomes D008466:Mechlorethamine D051379:Mice D010316:Particle Size D011355:Prodrugs D051381:Rats D017207:Rats, Sprague-Dawley D017382:Reactive Oxygen Species D016896:Treatment Outcome
nitrogen mustard nitrogen mustard prodrugs positive feedback neactive oxygen species nematological neoplasms