Boosting the Ferroptotic Antitumor Efficacy via Site-Specific Amplification of Tailored Lipid Peroxidation
Boosting the Ferroptotic Antitumor Efficacy via Site-Specific Amplification of Tailored Lipid Peroxidation
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DOI：
10.1021/acsami.9b10954
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发表时间：
2019-08-21
影响因子：
9.5
通讯作者：
Zhao, Yanjun
中科院分区：
文献类型：
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作者：
An, Yang;Zhu, Jundong;Zhao, Yanjun
铁凋亡是一种铁依赖性细胞死亡途径，可以根除某些对铁不敏感的癌细胞。铁蛋白分解诱导分子是定制的脂质过氧化物，其功效在缺氧实体瘤中受损并且缺乏肿瘤选择性。已经证明，药理学浓度的抗坏血酸盐（Asc）可以通过仅在肿瘤细胞外液中积累过氧化氢（H2 O2）来选择性地杀死癌细胞。据推测，Asc-induced，选择性富集的H2 O2在肿瘤耦合与Fe 3 + codelivery可以同时解决上述两个问题，通过提高羟基自由基和氧的水平，在肿瘤部位，以减轻过氧化反应的启动和传播，分别。本工作的目的是协同Asc与脂质包覆的磷酸钙（CaP）混合纳米载体的作用，所述脂质包覆的磷酸钙（CaP）混合纳米载体可以同时负载极性Fe 3+和非极性RSL 3，RSL 3是一种铁凋亡诱导剂，具有抑制脂质过氧化物修复酶（GPX 4）的机制。混合纳米载体在酸性条件（pH 5.0）下显示加速的货物释放。组合方法（Asc加纳米载体）在缺氧条件下产生显著升高水平的羟基自由基、脂质过氧化物和耗尽的谷胱甘肽，这伴随着模型4 T1细胞中的强细胞毒性（IC 50 = 1.2 +/- 0.2 μ M）。在4 T1荷瘤异种移植小鼠模型中，静脉内纳米载体递送加腹膜内Asc给药导致在肿瘤抑制方面的上级抗肿瘤性能，这不会对健康器官产生补充的不良作用。这项工作提供了一种新的方法来增强铁蛋白纳米药物对实体瘤的效力，而不会引起额外的副作用。
Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 +/- 0.2 mu M) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.