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

IF 8.7 1区医学 Q1 ENGINEERING, BIOMEDICAL

Materials Today Bio Pub Date : 2025-04-11 DOI:10.1016/j.mtbio.2025.101761

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

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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 in vitro and in vivo. 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.

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双响应纳米级超声造影剂作为氧化应激放大器增强brca精通卵巢癌的DNA损伤

基于PARP抑制剂（PARPi）的合成致死疗法在brca精通的卵巢癌中显示出有限的益处。为了加强PARPi的应用，我们建立了一种超声造影剂OLA- nds，用于递送PARPi olaparib (OLA)，通过阻断DNA修复来增强DNA损伤。OLA-NDs具有内源性pH-和外源性超声（US）对目标肿瘤的响应性，以及用于诊断和治疗结合的超声造影增强成像。OLA-NDs可以通过超声靶向微泡破坏（ultrasonic -targeted microbubble destruction， UTMD），上调NOX4诱导氧化应激，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ROS的产生，从而加剧DNA双链断裂（DSBs）并诱导线粒体介导的细胞凋亡。因此，UTMD与OLA-NDs联合应用在体内外均表现出显著的抗肿瘤作用。这种放大氧化损伤的联合策略通过促进DNA dsb和细胞凋亡提高了致死性，同时减少了不良反应，这将为PARPi在brca精通的卵巢癌中的临床应用提供新的见解。

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来源期刊

Materials Today Bio Multiple-

CiteScore

8.30

自引率

4.90%

发文量

303

审稿时长

30 days

期刊介绍： Materials Today Bio is a multidisciplinary journal that specializes in the intersection between biology and materials science, chemistry, physics, engineering, and medicine. It covers various aspects such as the design and assembly of new structures, their interaction with biological systems, functionalization, bioimaging, therapies, and diagnostics in healthcare. The journal aims to showcase the most significant advancements and discoveries in this field. As part of the Materials Today family, Materials Today Bio provides rigorous peer review, quick decision-making, and high visibility for authors. It is indexed in Scopus, PubMed Central, Emerging Sources, Citation Index (ESCI), and Directory of Open Access Journals (DOAJ).