Department of Pharmaceutics, School of Pharmacy, Air Force Medical University, Xi'an, 710032, China.
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, 710032, China.
Acta Biomater. 2023 Apr 1;160:265-280. doi: 10.1016/j.actbio.2023.02.025. Epub 2023 Feb 21.
Myocardial ischemia-reperfusion injury (MI/RI) seriously restricts the therapeutic effect of reperfusion. It is demonstrated that ferroptosis and apoptosis of cardiomyocytes are widely involved in MI/RI. Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Besides, transferrin receptor 1 (TfR1) is highly expressed in ischemic myocardium, and apoferritin (ApoFn) is a ligand of the transferrin receptor. In this study, CsA@ApoFn was prepared by wrapping cyclosporin A (CsA) with ApoFn and actively accumulated in ischemic cardiomyocytes through TfR1 mediated endoctosis in MI/RI mice. After entering cardiomyocytes, ApoFn in CsA@ApoFn inhibited ferroptosis of ischemic cardiomyocytes by increasing the protein expression of GPX4 and reducing the content of labile iron pool and lipid peroxides. At the same time, CsA in CsA@ApoFn attenuated the apoptosis of ischemic cardiomyocytes through recovering mitochondrial membrane potential and reducing the level of reactive oxygen species, which played a synergistic role with ApoFn in the treatment of MI/RI. In conclusion, CsA@ApoFn restored cardiac function of MI/RI mice by simultaneously blocking ferroptosis and apoptosis of cardiomyocytes. ApoFn itself not only served as a safe carrier to specifically deliver CsA to ischemic cardiomyocytes but also played a therapeutic role on MI/RI. CsA@ApoFn is proved as an effective drug delivery platform for the treatment of MI/RI. STATEMENT OF SIGNIFICANCE: Recent studies have shown that ferroptosis is an important mechanism of myocardial ischemia-reperfusion injury (MI/RI). Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Apoferritin, as a delivery carrier, can actively target to ischemic myocardium through binding with highly expressed transferrin receptor on ischemic cardiomyocytes. At the same time, apoferritin plays a protective role on ischemic cardiomyocytes by inhibiting ferroptosis. This strategy of killing two birds with one stone significantly improves the therapeutic effect on MI/RI while does not need more pharmaceutical excipients, which has the prospect of clinical transformation.
心肌缺血再灌注损伤（MI/RI）严重限制了再灌注的治疗效果。研究表明，心肌细胞的铁死亡和细胞凋亡广泛参与 MI/RI。因此，同时抑制心肌细胞的铁死亡和细胞凋亡可能是治疗 MI/RI 的一种有前途的策略。此外，转铁蛋白受体 1（TfR1）在缺血心肌中高表达，而脱铁铁蛋白（ApoFn）是转铁蛋白受体的配体。在这项研究中，通过用 ApoFn 包裹环孢素 A（CsA）制备 CsA@ApoFn，并通过 MI/RI 小鼠缺血心肌中的 TfR1 介导的内吞作用主动积累。进入心肌细胞后，CsA@ApoFn 中的 ApoFn 通过增加 GPX4 的蛋白表达并降低不稳定铁池和脂质过氧化物的含量来抑制缺血心肌的铁死亡。同时，CsA@ApoFn 中的 CsA 通过恢复线粒体膜电位和降低活性氧水平来减轻缺血心肌的细胞凋亡，这与 ApoFn 在 MI/RI 治疗中协同作用。总之，CsA@ApoFn 通过同时阻断心肌细胞的铁死亡和细胞凋亡来恢复 MI/RI 小鼠的心脏功能。ApoFn 本身不仅可以作为一种安全的载体，将 CsA 特异性递送到缺血心肌细胞，而且对 MI/RI 也具有治疗作用。CsA@ApoFn 被证明是一种有效的治疗 MI/RI 的药物递送平台。
最近的研究表明，铁死亡是心肌缺血再灌注损伤（MI/RI）的一个重要机制。因此，同时抑制心肌细胞的铁死亡和细胞凋亡可能是治疗 MI/RI 的一种有前途的策略。脱铁铁蛋白作为一种递送载体，可以通过与缺血心肌细胞上高表达的转铁蛋白受体结合，主动靶向缺血心肌。同时，脱铁铁蛋白通过抑制铁死亡对缺血心肌细胞发挥保护作用。这种一石二鸟的策略显著提高了 MI/RI 的治疗效果，同时不需要更多的药物赋形剂，具有临床转化的前景。
