用于癌症化疗-铁死亡联合治疗的二茂铁结合紫杉醇前药。
Ferrocene-Conjugated Paclitaxel Prodrug for Combined Chemo-Ferroptosis Therapy of Cancer.
发表日期：2024 Aug 27
作者：
Shaojin Lu, Dengyuan Hao, Qian Meng, Biyou Zhang, Xiujuan Xiang, Qing Pei, Zhigang Xie
来源：
Cellular & Molecular Immunology
摘要：
在此，我们通过紫杉醇（PTX）和二茂铁通过氧化还原响应性二硫键缀合开发了紫杉醇前药（PSFc）。 PSFc表现出酸增强芬顿反应的催化活性，并且能够通过与二硬脂酰磷酸乙醇胺-PEG2000组装形成稳定的纳米粒子（PSFc NPs）。被内吞后，PSFc NPs 可以释放 PTX 来促进细胞凋亡，以响应肿瘤细胞过度表达的氧化还原活性物质。同时，二茂铁介导的芬顿反应促进细胞内羟基自由基的积累和谷胱甘肽的消耗，从而导致铁死亡。与临床使用的紫杉醇相比，PSFc NPs通过化疗和铁死亡的联合作用表现出更有效的体内抗肿瘤效果。这项研究可能为整合不同肿瘤治疗方法来对抗恶性肿瘤的前药的简便设计提供见解。
Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.