The State Key Laboratory for Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410000, China.
ACS Nano. 2023 Jul 25;17(14):13792-13810. doi: 10.1021/acsnano.3c03443. Epub 2023 Jul 17.
Ferroptosis, as a type of programmed cell death process, enables effective damage to various cancer cells. However, we discovered that persistent oxidative stress during ferroptosis can upregulate the apurinic/apyrimidinic endonuclease 1 (APE1) protein that induces therapeutic resistance ("ferroptosis resistance"), resulting in an unsatisfactory treatment outcome. To address APE1-induced therapeutic resistance, we developed a GSH/APE1 cascade activated therapeutic nanoplatform (GAN). Specifically, the GAN is self-assembled by DNA-functionalized ultrasmall iron oxide nanoparticles and further loaded with drug molecules (drug-GAN). GSH-triggered GAN disassembly can "turn on" the catalysis of GAN to induce efficient lipid peroxidation (LPO) for ferroptosis toward the tumor, which could upregulate APE1 expression. Subsequently, upregulated APE1 can further trigger accurate drug release for overcoming ferroptosis resistance and inducing the recovery of near-infrared fluorescence for imaging the dynamics of APE1. Importantly, adaptive drug release can overcome the adverse effects of APE1 upregulation by boosting intracellular ROS yield and increasing DNA damage, to offset APE1's functions of antioxidant and DNA repair, thus leading to adaptive ferroptosis. Moreover, with overexpressed GSH and upregulated APE1 in the tumor as stimuli, the therapeutic specificity of ferroptosis toward the tumor is greatly improved, which minimized nonspecific activation of catalysis and excessive drug release in normal tissues. Furthermore, a switchable MRI contrast from negative to positive is in sync with ferroptosis activation, which is beneficial for monitoring the ferroptosis process. Therefore, this adapted imaging and therapeutic nanoplatform can not only deliver GSH/APE1-activated lipid peroxide mediated adaptive synergistic therapy but also provided a switchable MRI/dual-channel fluorescence signal for monitoring ferroptosis activation, drug release, and therapy resistance dynamics in vivo, leading to high-specificity and high-efficiency adaptive ferroptosis therapy.
铁死亡作为一种程序性细胞死亡过程，能够有效杀伤多种肿瘤细胞。然而，我们发现铁死亡过程中持续的氧化应激会上调诱导治疗抵抗的脱嘌呤/脱嘧啶内切酶 1（APE1）蛋白（“铁死亡抵抗”），导致治疗效果不理想。为了解决 APE1 诱导的治疗抵抗问题，我们开发了一种 GSH/APE1 级联激活治疗性纳米平台（GAN）。具体来说，GAN 由 DNA 功能化的超小氧化铁纳米颗粒自组装而成，并进一步负载药物分子（药物-GAN）。GSH 触发的 GAN 解体可以“开启”GAN 的催化作用，诱导肿瘤内有效的脂质过氧化（LPO）发生铁死亡，从而上调 APE1 的表达。随后，上调的 APE1 可以进一步触发精确的药物释放，以克服铁死亡抵抗并诱导近红外荧光恢复以成像 APE1 的动力学。重要的是，适应性药物释放可以通过增加细胞内 ROS 产生和增加 DNA 损伤来克服 APE1 上调的不利影响，从而抵消 APE1 的抗氧化和 DNA 修复功能，从而导致适应性铁死亡。此外，肿瘤中过表达的 GSH 和上调的 APE1 作为刺激物，极大地提高了铁死亡对肿瘤的治疗特异性，最大限度地减少了正常组织中催化的非特异性激活和过度药物释放。此外，从负到正的可切换 MRI 对比与铁死亡激活同步，有利于监测铁死亡过程。因此，这种可切换的 MRI/双通道荧光信号成像和治疗纳米平台不仅可以提供 GSH/APE1 激活的脂质过氧化物介导的适应性协同治疗，还可以用于监测体内铁死亡激活、药物释放和治疗抵抗动力学，从而实现高特异性和高效的适应性铁死亡治疗。
