'Mito-Bomb': a novel mitochondria-targeting nanosystem for ferroptosis-boosted sonodynamic antitumor therapy

作者全名："Wang, Jianxin; Zhao, Zhiyu; Liu, Yan; Cao, Xinyu; Li, Fuxin; Ran, Haitao; Cao, Yang; Wu, Changjun"

作者地址："[Wang, Jianxin; Zhao, Zhiyu; Liu, Yan; Cao, Xinyu; Li, Fuxin; Wu, Changjun] Harbin Med Univ, Dept Ultrasound, Affiliated Hosp 1, Harbin 150001, Peoples R China; [Ran, Haitao; Cao, Yang] Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound Imaging, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China"

通信作者："Wu, CJ (通讯作者)，Harbin Med Univ, Dept Ultrasound, Affiliated Hosp 1, Harbin 150001, Peoples R China.; Cao, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound Imaging, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China."

来源：DRUG DELIVERY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000857147100001

JCR分区：Q1

影响因子：6

年份：2022

卷号：29

期号：1

开始页：3111

结束页：3122

文献类型：Article

关键词：Sonodynamic therapy; ferroptosis; reactive oxygen species; GPX4; RSL-3

摘要："Mitochondria play an important role in regulating tumor cell death and metabolism so that they can be potential therapeutic targets. Sonodynamic therapy (SDT) represents an attractive antitumor method that induces apoptosis by producing highly toxic reactive oxygen species (ROS). Mitochondria-targeting SDT can cause oxidative damage and improve the efficiency of tumor therapy. However, due to the nonselective distribution of nanosystems and the anti-apoptotic mechanism of cancer cells, the therapeutic effect of SDT is not ideal. Therefore, we proposed a novel mitochondria-targeting nanosystem ('Mito-Bomb') for ferroptosis-boosted SDT. Sonosensitizer IR780 and ferroptosis activator RSL-3 were both encapsulated in biocompatible poly(lactic-co-glycolic acid) (PLGA) nanoparticles to form 'Mito-Bomb' (named IRP NPs). IR780 in this nanosystem was used to mediate mitochondria-targeting SDT. RSL-3 inhibited the activity of GPX4 in the antioxidant system to induce ferroptosis of tumor cells, which could rewire tumor metabolism and make tumor cells extremely sensitive to SDT-induced apoptosis. Notably, we also found that RSL-3 can inhibit hypoxia inducible factor-1 alpha (HIF-1 alpha) and induce ROS production to improve the efficacy of SDT to synergistically antitumor. RSL-3 was applied as a 'One-Stone-Three-Birds' agent for cooperatively enhanced SDT against triple-negative breast cancer. This study presented the first example of RSL-3 boosting mitochondria-targeting SDT as a ferroptosis activator. The 'Mito-Bomb' biocompatible nanosystem was expected to become an innovative tumor treatment method and clinical transformation."

基金机构："National Natural Science Foundation of China [82071926, 81630047]; University Innovation Team Plans of Chongqing [CXTDG201602007]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 82071926 and 81630047), the University Innovation Team Plans of Chongqing under grants (No. CXTDG201602007.)"