Amorphous ferric oxide-coating selenium core-shell nanoparticles: a self-preservation Pt(iv) platform for multi-modal cancer therapies through hydrogen peroxide depletion-mediated anti-angiogenesis, apoptosis and ferroptosis
Amorphous ferric oxide-coating selenium core-shell nanoparticles: a self-preservation Pt(iv) platform for multi-modal cancer therapies through hydrogen peroxide depletion-mediated anti-angiogenesis, apoptosis and ferroptosis
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非晶态三氧化二铁包覆硒核壳纳米颗粒：一种自我保护的 Pt(iv) 平台，通过过氧化氢耗竭介导的抗血管生成、细胞凋亡和铁死亡进行多模式癌症治疗
DOI：
10.1039/d2nr01837c
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发表时间：
2022-07-12
期刊：
影响因子：
6.7
通讯作者：
Zhang, Guilong
中科院分区：
文献类型：
--
作者：
Xu, Zhaowei;Li, Qingdong;Zhang, Guilong
一种自我保护的Pt（iv）纳米平台--无定形氧化铁包覆硒核壳纳米颗粒（iAIO@NSe-Pt）被开发用于H2 O2耗尽介导的肿瘤抗血管生成、细胞凋亡和铁凋亡。在进入血液后，氧化铁壳有效地阻断了Pt（iv）前药与还原分子的接触，然后避免了Pt（iv）前药的失活并增加了其在肿瘤中的积累。iAIO@NSe-Pt进入癌细胞后引起一系列级联反应：（1）由于肿瘤微环境呈弱酸性，iAIO@NSe-Pt表面的AIO迅速溶解，释放出丰富的Fe（ii），进而催化细胞内H2 O2转化为高毒性OH，导致细胞内H2 O2缺乏，细胞铁凋亡。(2)铂（iv）前药暴露，并通过消耗GSH迅速还原为高毒性Pt（ii）。这一过程使GPX 4失活，促进ROS积累，并进一步加速铁凋亡。此外，生成的Pt（ii）快速抑制DNA复制，实现有效的凋亡细胞死亡。同时，Pt（ii）使SOD 1失活，从而阻断了细胞H2 O2的合成，加速了ROS（超氧阴离子自由基）的积累。(3)细胞内H2 O2的缺乏可显著抑制血管内皮生长因子-A（VEGF-A）的表达，阻断肿瘤血管生成，从而提高肿瘤的抗肿瘤效果。(4)在这样的级联反应之后，暴露的NSe连续破坏线粒体呼吸并抑制癌症血管生成，进一步诱导癌细胞死亡。总的来说，我们的功能和机械研究表明，iAIO@NSe-Pt在体外和体内表现出优异的肿瘤靶向，生物相容性和抗肿瘤效率，并为H2 O2耗尽介导的肿瘤抗血管生成，细胞凋亡和铁凋亡提供了一个新的自我保护Pt（iv）纳米平台的例子，显示出未来临床应用的巨大前景。
A self-preservation Pt(iv) nanoplatform, amorphous ferric oxide-coating selenium core-shell nanoparticles (iAIO@NSe-Pt), was developed for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis. Upon entry into the blood, the ferric oxide shell effectively blocked the contact Pt(iv) prodrug with reduced molecules, then avoided the inactivation of the Pt(iv) prodrug and increased its accumulation in the tumor. After entering cancer cells, iAIO@NSe-Pt caused a series of cascade reactions: (1) AIO on the surface of iAIO@NSe-Pt quickly dissolved, released an abundance of Fe(ii) because of the weakly acidic tumor microenvironment, and then catalyzed cellular H2O2 into highly toxic OH, resulting in cellular H2O2 deficiency and cell ferroptosis. (2) The platinum(iv) prodrugs were exposed and quickly reduced to highly toxic Pt(ii) by depleting GSH. This process inactivated GPX4, promoted ROS accumulation, and further accelerated ferroptosis. In addition, the generated Pt(ii) quickly inhibited DNA replication, achieving effective apoptotic cell death. Meanwhile, Pt(ii) inactivated SOD1, which blocked the synthesis of cellular H2O2 and accelerated ROS (superoxide anion radical) accumulation. (3) The deficiency of cellular H2O2 significantly inhibited the expression of vascular endothelial growth factor-A (VEGF-A), blocking tumor angiogenesis and then improving the anticancer effect. (4) After such a cascade reaction, the exposed NSe successively disrupted mitochondrial respiration and inhibited cancer angiogenesis, further inducing cancer cell death. Collectively, our functional and mechanical investigation suggested that iAIO@NSe-Pt exhibits excellent tumor targeting, biocompatibility and anti-tumor efficiency in vitro and in vivo, and provides a novel example of a self-preservation Pt(iv) nanoplatform for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis, showing great promise for future clinical use.