Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, 264003, P. R. China.
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University and Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui 230022, P. R. China.
Nanoscale. 2022 Aug 18;14(32):11600-11611. doi: 10.1039/d2nr01837c.
A self-preservation Pt(IV) nanoplatform, amorphous ferric oxide-coating selenium core-shell nanoparticles (iAIO@NSe-Pt), was developed for HO 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 HO into highly toxic ˙OH, resulting in cellular HO 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 HO and accelerated ROS (superoxide anion radical) accumulation. (3) The deficiency of cellular HO 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 and , and provides a novel example of a self-preservation Pt(IV) nanoplatform for HO depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis, showing great promise for future clinical use.
一种自我保护的 Pt(IV)纳米平台，无定形氧化铁-硒核壳纳米粒子（iAIO@NSe-Pt），被开发用于 HO 耗竭介导的肿瘤抗血管生成、细胞凋亡和铁死亡。进入血液后，氧化铁壳有效地阻止了 Pt(IV)前药与还原分子的接触，从而避免了 Pt(IV)前药的失活并增加了其在肿瘤中的积累。进入癌细胞后，iAIO@NSe-Pt 引起了一系列级联反应：（1）iAIO@NSe-Pt 表面的 AIO 迅速溶解，由于弱酸性的肿瘤微环境，释放出大量的 Fe(II)，然后催化细胞内的 HO 生成高度毒性的˙OH，导致细胞内 HO 缺乏和细胞铁死亡。（2）铂(IV)前药被暴露并迅速被还原为高度毒性的 Pt(II)，通过耗尽 GSH。这个过程使 GPX4 失活，促进 ROS 积累，进一步加速铁死亡。此外，生成的 Pt(II)迅速抑制 DNA 复制，实现有效的细胞凋亡死亡。同时，Pt(II)使 SOD1 失活，阻止了细胞内 HO 的合成并加速了 ROS（超氧阴离子自由基）的积累。（3）细胞内 HO 的缺乏显著抑制了血管内皮生长因子-A（VEGF-A）的表达，阻断了肿瘤血管生成，从而提高了抗癌效果。（4）经过这样的级联反应，暴露的 NSe 相继破坏线粒体呼吸并抑制肿瘤血管生成，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 具有优异的肿瘤靶向性、生物相容性和抗肿瘤效率，并为 HO 耗竭介导的肿瘤抗血管生成、细胞凋亡和铁死亡提供了一种新型的自我保护 Pt(IV)纳米平台，为未来的临床应用提供了新的范例。
