Wang Wenhao, Fu Fangqin, Huang Zhengwei, Wang Wenhua, Chen Minglong, Yue Xiao, Fu Jintao, Feng Xiaoqian, Huang Ying, Wu Chuanbin, Pan Xin
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, China.
College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong, China.
ACS Nano. 2022 May 24;16(5):8370-8387. doi: 10.1021/acsnano.2c02634. Epub 2022 May 15.
Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system X) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.
通过催化芬顿反应进行的铁死亡疗法已成为一种有前景的肺腺癌（ADC）肿瘤消除策略。然而，芬顿反应效率不理想、细胞内抗氧化系统强大以及肺部药物蓄积不足限制了铁死亡的治疗效果。为了解决这些问题，通过在负载二茂铁（Fc）和氟伐他汀的阳离子纳米结构脂质载体（NLC）核心表面自发吸附由基质金属蛋白酶2响应性明胶和谷氨酸（Glu）组成的仿生蛋白冠（PC），提出了一种可吸入纳米反应器。制备的Fc-NLC(F)@PC可雾化至肺部病变，药物蓄积量高2.6倍，脂质过氧化物生成量提高3.2倍，以增强铁死亡治疗效果。从机制上讲，氟伐他汀被证明可抑制单羧酸转运蛋白4介导的乳酸外流，诱导肿瘤酸中毒以促进Fc催化的活性氧生成，同时发现细胞外Glu浓度升高可抑制xCT（系统X）功能，并通过抑制谷胱甘肽合成进一步破坏肿瘤抗氧化系统。线粒体功能障碍和细胞膜损伤参与了纳米反应器驱动的铁死亡细胞死亡过程。在原位肺ADC肿瘤模型中证实了肿瘤酸中毒和抗氧化系统破坏联合作用增强的抗肿瘤效果。总体而言，所提出的纳米反应器突出了用于局部肺ADC治疗的肺部给药方法，并强调了铁死亡疗法的巨大潜力。
