Harnessing transcription factor-driven ROS for synergistic multimodal lung cancer treatment

• Published in: Journal of controlled release 2024-10, Vol.374, p.489-504
• Main Authors: Zhou, Ye, Wang, Simeng, Guo, Jiahua, Li, Chenghao, Sui, Mengjun, Zeng, Zekun, Dang, Hui, Gu, Qingqing, Zhu, Jian, Cheng, Yangyang, Hou, Peng
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Combined Modality Therapy; Docetaxel - administration & dosage; Docetaxel - pharmacokinetics; Docetaxel - pharmacology; Docetaxel - therapeutic use; Drug delivery; Drug Liberation; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mice, Inbred BALB C; Mice, Nude; Multimodal cancer therapy; Nanoparticles; NF-E2-Related Factor 2 - metabolism; NRF2-targeted; Prodrugs - administration & dosage; Prodrugs - therapeutic use; Reactive Oxygen Species - metabolism; ROS-responsive; Self-sustainable strategy
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.08.035

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond. A transcription factor-driven ROS self-sustainable strategy developed herein empowers the flawless blend of targeted therapy, chemotherapy, and radiotherapy, three first-line therapies for lung cancer. [Display omitted] •A lipid nanodrug loaded with a targeted inhibitor and a chemo-prodrug is developed.•This nanodrug enables a transcription factor-driven ROS self-sustainable motion.•This ROS self-sustainable motion in-turn improves chemo-prodrug activation.•This nanodrug facilitates synergistic multimodal lung cancer therapy.