Department of Pharmaceutical Analysis , China Pharmaceutical University , Nanjing 210009 , China.
Department of Natural Medicinal Chemistry , China Pharmaceutical University , Nanjing 211198 , China.
ACS Appl Mater Interfaces. 2019 Nov 20;11(46):42873-42884. doi: 10.1021/acsami.9b12469. Epub 2019 Nov 11.
Ferroptosis is an iron-dependent cell death caused by accumulation of lipid peroxidation (LPO), which is a new strategy for cancer treatment. Th current ferroptosis therapy nanodevices have low efficiency and side effects generally. Hence, we developed a Black Hole Quencher (BHQ)-based fluorescence "off-on" nanophotosensitizer complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib (Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib. IR780-Hex anchored to the mitochondrial membrane, which would contribute to amplifying the efficiency of the photosensitizer. When NIR irradiation was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO burst. A malondialdehyde test showed that LPO in complex assembly-treated cells was explosive and increased about 18-fold compared to the control. The accumulation process of particles was monitored by an IR780-Hex photosensitizer, which showed an excellent tumor target ability by magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib in a nanodevice was increased about 26-fold compared to the control group. Importantly, the complex assembly effectively inhibits tumor growth in the breast tumor mouse model. This work would provide ideas in designing nanomedicines for the ferroptosis treatment of cancer.
铁死亡是一种由脂质过氧化（LPO）积累引起的铁依赖性细胞死亡，这是一种新的癌症治疗策略。目前的铁死亡治疗纳米器件效率低，通常有副作用。因此，我们开发了一种基于黑洞猝灭剂（BHQ）的荧光“关-开”纳米光敏剂复合物组装体（CSO-BHQ-IR780-Hex/MIONPs/Sor）。CSO 连接的 BHQ-IR780-Hex 和负载磁性氧化铁纳米颗粒（MIONPs）和索拉非尼（Sor）形成了一个非常简洁的功能化递送系统。CSO-BHQ-IR780-Hex 被 GSH 攻击分解，并释放出 IR780-Hex、MIONPs 和索拉非尼。IR780-Hex 锚定在线粒体膜上，这有助于提高光敏剂的效率。当给予 CSO-BHQ-IR780-Hex/MIONPs/Sor 处理的细胞近红外照射时，铁供应增加，xCT/GSH/GPX-4 系统被触发，大量 LPO 爆发。丙二醛测试表明，复合物组装处理的细胞中的 LPO 是爆炸性的，比对照组增加了约 18 倍。通过 IR780-Hex 光敏剂监测颗粒的积累过程，该光敏剂通过体内纳米器件的磁性显示出优异的肿瘤靶向能力。有趣的是，与对照组相比，纳米器件中索拉非尼的半衰期增加了约 26 倍。重要的是，该复合物组装体有效地抑制了乳腺癌小鼠模型中的肿瘤生长。这项工作将为设计用于癌症铁死亡治疗的纳米药物提供思路。
