Dual-targeted nanoparticulate drug delivery systems for enhancing triple-negative breast cancer treatment

Shunzhe Zheng, Meng Li, Wenqian Xu, Jiaxin Zhang, Guanting Li, Hongying Xiao, Xinying Liu, Jianbin Shi, Fengli Xia, Chutong Tian, Ken ichiro Kamei

Research output: Contribution to journalArticlepeer-review


The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.

Original languageEnglish (US)
Pages (from-to)371-385
Number of pages15
JournalJournal of Controlled Release
StatePublished - Jul 2024


  • DNA damage repair
  • DNA damage therapy
  • Homologous recombination
  • ROS self-amplification
  • Translational nanomedicine

ASJC Scopus subject areas

  • Pharmaceutical Science


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