CAS Key Laboratory of Magnetic Materials and Devices, & Key Laboratory of Additive Manufacturing Materials of Zhejiang Province, & Division of Functional Materials and Nanodevices, Ningbo Institute of Materials Technology and Engineering , Chinese Academy of Sciences , 1219 Zhong-guan West Road , Ningbo , Zhejiang 315201 , China.
Laboratory of Molecular Imaging and Nanomedicine , National Institute of Biomedical Imaging and Bioengineering , National Institutes of Health, Bethesda , Maryland 20892 , United States.
ACS Nano. 2018 Nov 27;12(11):11355-11365. doi: 10.1021/acsnano.8b06201. Epub 2018 Nov 5.
Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe, Fe, and HO) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded FeO/GdO hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood-brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin αβ-mediated endocytosis and then release Fe, Fe, and CDDP upon endosomal uptake and degradation. Fe and Fe can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce HO to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI monitoring).
癌症是全球发病率和死亡率的主要原因之一，但由于现有癌症疗法存在问题，需要更多的癌症疗法来补充现有的治疗方案。在此，我们将铁死亡疗法 (FT) 视为一种癌症疗法，并假设通过同时增加癌细胞中所有反应物（Fe、Fe 和 HO）的局部浓度，可以显著提高 FT 疗效。因此，本研究中利用了芬顿反应可加速磁性纳米粒子，即负载顺铂 (CDDP) 的 FeO/GdO 杂化纳米粒子与乳铁蛋白 (LF) 和 RGD 二聚体 (RGD2) 的缀合 (FeGd-HN@Pt@LF/RGD2)，用于原位脑肿瘤的 FT。由于其粒径小（6.6nm）和 LF 受体介导的转胞吞作用，FeGd-HN@Pt@LF/RGD2 纳米粒子能够穿过血脑屏障。FeGd-HN@Pt@LF/RGD2 可以通过整合素 αβ 介导的内吞作用被内化到癌细胞中，然后在内涵体摄取和降解时释放 Fe、Fe 和 CDDP。Fe 和 Fe 可以直接参与芬顿反应，而 CDDP 可以间接产生 HO 以进一步加速芬顿反应。芬顿反应的加速产生活性氧诱导癌细胞死亡。FeGd-HN@Pt@LF/RGD2 成功地将参与芬顿反应的反应物递送到肿瘤部位，导致肿瘤生长显著抑制。最后，利用纳米粒子的固有磁共振成像（MRI）能力来评估和监测肿瘤对 FT 的反应（自 MRI 监测）。
