Li Ning, Gao Dong, Li Chen, Wang Baiqi, Li Boying, Bao Benkai, Wu Manman, Li Mengying, Xing Chengfen
School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300401, P. R. China.
Key Laboratory of Hebei Province for Molecular Biophysics, Institute of Biophysics, Hebei University of Technology, Tianjin 300401, P. R. China.
ACS Appl Mater Interfaces. 2022 May 11. doi: 10.1021/acsami.1c23146.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activating therapy has received wide attention due to its capacity to precisely induce cancer cell apoptosis. However, drug resistance and the poor pharmacokinetic properties of TRAIL protein are obstacles in TRAIL-based therapy for cancer. Herein, a strategy is developed to remotely control and specifically initiate TRAIL-mediated apoptotic signaling to promote TRAIL-resistant cancer cell apoptosis using near-infrared (NIR) light-absorbing conjugated polymer nanoparticles (CPNs). Upon 808 nm laser excitation, the promoter 70 kilodalton heat shock protein (HSP70) initiates transcription of the TRAIL gene in response to heat shock, thereby expressing TRAIL protein in breast cancer cells, which activates the TRAIL-mediated apoptosis signaling pathway. Simultaneously, the CPNs locally release W-7, which targets calmodulin (CaM) and further promotes caspase-8 cleavage and enhances cancer cell apoptosis. Both and results demonstrate that CPNs/W-7/pTRAIL produces an excellent synergistic therapeutic effect on breast cancer upon near-infrared light with low toxicity. Therefore, this work provides a strategy for overcoming drug resistance through dual-targeting TRAIL-mediated apoptotic signaling in breast cancer.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）激活疗法因其精确诱导癌细胞凋亡的能力而受到广泛关注。然而，TRAIL蛋白的耐药性和较差的药代动力学性质是基于TRAIL的癌症治疗中的障碍。在此，开发了一种策略，利用近红外（NIR）光吸收共轭聚合物纳米颗粒（CPN）远程控制并特异性启动TRAIL介导的凋亡信号，以促进对TRAIL耐药的癌细胞凋亡。在808 nm激光激发下，启动子70千道尔顿热休克蛋白（HSP70）响应热休克启动TRAIL基因的转录，从而在乳腺癌细胞中表达TRAIL蛋白，激活TRAIL介导的凋亡信号通路。同时，CPN局部释放W-7，其靶向钙调蛋白（CaM）并进一步促进半胱天冬酶-8的裂解，增强癌细胞凋亡。体外和体内结果均表明，CPN/W-7/pTRAIL在近红外光照射下对乳腺癌产生了优异的协同治疗效果且毒性较低。因此，这项工作为通过双重靶向TRAIL介导的凋亡信号克服乳腺癌耐药性提供了一种策略。
