School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China.
Kazan State Medical University, 49 Butlerova Street, Kazan, RT 420012, Russia.
ACS Nano. 2024 Mar 5;18(9):7011-7023. doi: 10.1021/acsnano.3c10142. Epub 2024 Feb 23.
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G/G phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
铁死亡治疗自铁死亡概念提出以来已得到广泛研究。然而，由于黑素细胞和暂态细胞亚群对铁依赖性氧化应激具有抗性，异质性和可塑性黑素瘤中铁死亡诱导的治疗效果受到了损害。在这里，我们报告了一种改变表型的脂质体纳米药物，通过诱导衰老使铁死亡抗性的黑素瘤细胞亚群易受脂质过氧化作用的影响。该策略涉及将细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂（帕博西尼）和铁死亡诱导剂（金诺芬）在 cRGD 肽修饰的靶向脂质体中进行比率共包封。两种药物在 B16F10 黑素瘤细胞模型中表现出协同抗癌作用，这一点通过组合指数分析得到了证明（<1）。脂质体能够以靶向方式将两种药物高效递送至 B16F10 细胞中。随后，脂质体有效地诱导了细胞内氧化还原失衡和脂质过氧化。帕博西尼显著地将细胞周期阻滞在 G1/G0 期，通过诱导衰老使金诺芬引起的铁死亡敏感化。同时，帕博西尼耗尽细胞内谷胱甘肽（GSH）并减少烟酰胺腺嘌呤二核苷酸磷酸（NADPH），进一步促进铁死亡。这一概念验证也在 B16F10 荷瘤小鼠模型中得到了证明。目前的工作为通过操纵细胞可塑性有效治疗异质性黑素瘤提供了一种有前途的铁死亡靶向策略。
