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双响应纳米级超声造影剂作为氧化应激放大器用于增强BRCA功能正常的卵巢癌中的DNA损伤

Dual-responsive nanoscale ultrasound contrast agent as an oxidative stress amplifier for enhanced DNA damage in BRCA-proficient ovarian cancer.

作者信息

Zhang Jialu, Wang Xiaoxuan, Guo Lu, Xiao Shan, Meng Dong, Shang Mengmeng, Sun Xiao, Shi Dandan, Zhao Yading, Liu Rui, Huang Shuting, Zeng Xinyu, Li Jie

机构信息

Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.

Department of Ultrasound, Qilu Hospital (Qingdao) of Shandong University, Qingdao, Shandong, 266035, China.

出版信息

Mater Today Bio. 2025 Apr 11;32:101761. doi: 10.1016/j.mtbio.2025.101761. eCollection 2025 Jun.

DOI:10.1016/j.mtbio.2025.101761
PMID:40270892
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12017913/
Abstract

PARP inhibitor (PARPi)-based synthetic lethal therapies have displayed limited benefits in BRCA-proficient ovarian cancer. To potentiate the application of PARPi, an ultrasound contrast agent OLA-NDs for delivery of the PARPi olaparib (OLA) was established for enhancing DNA damage by blocking DNA repair. OLA-NDs were endowed with endogenous pH- and exogenous ultrasound (US)-responsiveness to target tumors, as well as contrast-enhanced US imaging for diagnostic and therapeutic integration. OLA-NDs could upregulate NOX4 to induce oxidative stress and sensitize BRCA wild-type A2780 cells to DNA oxidative damage through the utilization of ultrasound-targeted microbubble destruction (UTMD). In addition, the strategy further increased ROS production by interfering with mitochondrial function, thereby exacerbating DNA double-strand breaks (DSBs) and inducing mitochondria-mediated apoptosis. As a consequence, the combined application of UTMD and OLA-NDs demonstrated significant antitumor effects and . This combined strategy of amplifying oxidative damage improved lethality by promoting DNA DSBs and apoptosis with reduced adverse side effects, which would provide new insight for the clinical application of PARPi in BRCA-proficient ovarian cancer.

摘要

基于聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的合成致死疗法在BRCA基因功能正常的卵巢癌中显示出有限的疗效。为了增强PARPi的应用效果，一种用于递送PARPi奥拉帕利（OLA）的超声造影剂OLA-纳米金刚石被研发出来，通过阻断DNA修复来增强DNA损伤。OLA-纳米金刚石具有内源性pH响应和外源性超声（US）响应，可靶向肿瘤，同时具备超声造影增强成像功能，实现诊断与治疗一体化。OLA-纳米金刚石可上调NOX4以诱导氧化应激，并通过利用超声靶向微泡破坏（UTMD）使BRCA野生型A2780细胞对DNA氧化损伤敏感。此外，该策略通过干扰线粒体功能进一步增加活性氧（ROS）的产生，从而加剧DNA双链断裂（DSB）并诱导线粒体介导的凋亡。因此，UTMD与OLA-纳米金刚石的联合应用显示出显著的抗肿瘤效果。这种放大氧化损伤的联合策略通过促进DNA DSB和凋亡提高了杀伤力，同时减少了副作用，这将为PARPi在BRCA基因功能正常的卵巢癌临床应用中提供新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/6f31b78a21b6/gr8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/6f31b78a21b6/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/e1a1b3748611/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/61a597775e24/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/e1bac0a99814/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/48d5d1690b99/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/772d6f1e74cd/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/b2c286e63922/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/e9c24b36c4ea/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/5d486dbad4c8/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cb7/12017913/6f31b78a21b6/gr8.jpg

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