Rapamycin-reinforced ferroptosis assisted by a lysosome-controlled disintegratable micelle in autophagy-dependent/independent manners
Rapamycin-reinforced ferroptosis assisted by a lysosome-controlled disintegratable micelle in autophagy-dependent/independent manners
复制标题
溶酶体控制的可崩解胶束以自噬依赖性/独立方式辅助雷帕霉素增强的铁死亡
DOI：
10.1016/j.apmt.2021.101066
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发表时间：
2021-06
影响因子：
8.3
通讯作者：
Wang Shan
中科院分区：
文献类型：
--
作者：
Jiang Renting;Li Xin;Hu Dun;Zhu Min;Zhou Di;Yuan Mengying;Hu Xin;Nie Shengdan;Liu Jiajia;Xiang Haoyue;Yang Hua;Zhang Yi;Wang Shan
上调癌细胞对铁下垂的易感性是提高铁下垂药物系统抗癌效果的关键。目前，要以预期的机制优化铁下垂的增敏剂，并通过简便的纳米载体改善转运，仍然在很大程度上依赖于偶然发现和重复分配。在这里，我们使用单宁酸(TA)为模板的硅纳米颗粒作为纳米核，通过溶酶体控制的可分解Fe3+@erastin@雷帕霉素胶束(REFSM)，通过自噬依赖/非吞噬途径鉴定雷帕霉素是一种铁下垂增敏剂。所制备的ReFSM对溶酶体的酸性条件和酶系统做出反应，允许Fe3+和Erastin的释放来刺激铁下垂，而雷帕霉素通过刺激铁素噬菌体和脂噬作用而增强了这一作用，并抑制了HIF-1α。雷帕霉素增强的铁性下垂被证明是对过氧化氢过载的癌细胞特异的。此外，雷帕霉素的引入降低了胶束的正电荷，改善了胶束在肿瘤中的分布。可控的解离和改进的电荷保证了其在微量Erastin(0.3mgkg−1)和雷帕霉素(2.2mgkg−1)下的抗癌效果，并将系统毒性降至最低。该模板展示了雷帕霉素的多种药理机制，控制了雷帕霉素的释放，改善了雷帕霉素在体内的分布，为雷帕霉素作为增敏剂增强铁下垂提供了一个通用的平台。
Upregulating the susceptibility of cancer cells to ferroptosis is crucial to upgrade anti-cancer efficiency of ferroptosis drug system. At present, optimizing the sensitizer for ferroptosis with expected mechanism and improved transport via facile nanocarriers still heavily rely on serendipitous discovery and repetitious assignment. Herein, we employ the tannic acid (TA)-templated silicon nanoparticle as nanocore to descend the lysosome-controlled disintegratable Fe3+@erastin@rapamycin micelles (REFSM) to identify rapamycin as a ferroptosis sensitizer through autophagy-dependent/independent pathways. The as-prepared REFSM dissociates responding to the acidic condition and enzyme system of lysosomes, permitting Fe3+and erastin release to irritate ferroptosis, which is reinforced by released rapamycin via irritating ferritinophagy and lipophagy, and suppressing HIF-1α. The rapamycin-reinforced ferroptosis is demonstrated to be specific to H2O2-overloaded cancer cells. Moreover, the introduction of rapamycin reduces the positive charge of micelle and improves its distribution in tumors. Both the controllable dissociation and the improved charge of REFSM ensure its anti-cancer efficiency at trace amount of erastin (0.3 mg kg−1) and rapamycin (2.2 mg kg−1) and minimize the systematic toxicity. This archetypical template provides a versatile platform for rapamycin as sensitizer to enhance ferroptosis by displaying its multiple pharmacological mechanism, controlling its release and improving its distributionin vivo.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
19
作者：
Yang WS;Stockwell BR
通讯作者：
Stockwell BR
金-DNA 纳米向日葵通过可控转化实现高效基因沉默
影响因子：
13.6
作者：
Huo, Shuaidong;Gong, Ningqiang;Liang, Xing-Jie
通讯作者：
Liang, Xing-Jie
影响因子：
9.5
作者：
An, Yang;Zhu, Jundong;Zhao, Yanjun
通讯作者：
Zhao, Yanjun
影响因子：
16.6
作者：
Guo, Junling;Ping, Yuan;Caruso, Frank
通讯作者：
Caruso, Frank