Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
School of Medicine, Xiamen University, Xiamen 361102, China.
Nanoscale Horiz. 2023 May 30;8(6):783-793. doi: 10.1039/d2nh00494a.
Ferroptosis is one critical kind of regulated cell death for tumor suppression, yet it still presents challenges of low efficiency due to the intracellular alkaline pH and aberrant redox status. Herein, we reported a carbonic anhydrase IX (CA IX)-targeted nanovesicle (PAHC NV) to potentiate ferroptosis by remodeling the intracellular environment. CA IX inhibitor 4-(2-aminoethyl) benzene sulfonamide (AEBS) was anchored onto nanovesicles loaded with hemoglobin (Hb) and chlorin e6 (Ce6). Upon reaching tumor regions, PAHC could be internalized by cancer cells specifically by means of CA IX targeting and intervention. Afterwards, the binding of AEBS could elicit intracellular acidification and alter redox homeostasis to boost the lipid peroxidation (LPO) level, thus aggravating the ferroptosis process. Meanwhile, Hb served as an iron reservoir that could efficiently evoke ferroptosis and release O to ameliorate tumor hypoxia. With the help of self-supplied O, Ce6 produced a plethora of O for enhanced photodynamic therapy, which in turn favored LPO accumulation to synergize ferroptosis. This study presents a promising paradigm for designing nanomedicines to heighten ferroptosis-based synergetic therapeutics through remodeling the intracellular environment.
铁死亡是一种重要的肿瘤抑制性细胞死亡方式，但由于细胞内的碱性 pH 值和异常的氧化还原状态，其效率仍然较低。在此，我们报道了一种碳酸酐酶 IX（CA IX）靶向的纳米囊泡（PAHC NV），通过重塑细胞内环境来增强铁死亡。将 CA IX 抑制剂 4-(2-氨基乙基)苯磺酰胺（AEBS）锚定在载有血红蛋白（Hb）和氯乙酮（Ce6）的纳米囊泡上。当到达肿瘤区域时，PAHC 可以通过 CA IX 靶向和干预被癌细胞特异性内化。之后，AEBS 的结合可以引起细胞内酸化并改变氧化还原稳态，以提高脂质过氧化（LPO）水平，从而加剧铁死亡过程。同时，Hb 作为铁库，可以有效地引发铁死亡并释放 O 以改善肿瘤缺氧。在自供给 O 的帮助下，Ce6 产生大量 O 以增强光动力治疗，这反过来又有利于 LPO 积累，以协同铁死亡。本研究提出了一种有前途的范例，通过重塑细胞内环境来设计纳米药物，以提高基于铁死亡的协同治疗效果。
