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Updated: Jun 24, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Dual-targeted nanoparticulate drug delivery systems for enhancing triple-negative breast cancer treatment
Shunzhe Zheng1, Meng Li1, Wenqian Xu1
1Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Abstract:
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.
Insights
This study introduces SJNP, a novel nanostructure that combines DNA damage and mitochondrial dysfunction to fight cancer. SJNP effectively targets triple-negative breast cancer with low toxicity by inhibiting DNA repair and increasing oxidative stress.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- DNA repair mechanisms, particularly homologous recombination (HR), limit the effectiveness of DNA-damaging cancer drugs like SN38.
- Tumor cells possess robust repair pathways that can lead to therapeutic resistance.
Purpose of the Study:
- To develop a novel nanostrategy with binary tumor-killing mechanisms to overcome drug resistance and enhance cancer treatment.
- To investigate the synergistic effects of combining a topoisomerase I inhibitor (SN38) with a BET inhibitor (JQ-1) delivered via a nanostructure.
Main Methods:
- Synthesis of SN38 and JQ-1 prodrugs conjugated with linoleic acid (LA) via a cinnamaldehyde thioacetal (CT) bond.
- Co-assembly of prodrugs into a synergistic nanostructure (SJNP) for co-delivery.
- Evaluation of SJNP efficacy at cellular and tissue levels, including disruption of BRD4, downregulation of BRCA1/RAD51, and induction of ROS-mediated mitochondrial dysfunction.
Main Results:
- SJNP effectively disrupts BRD4, leading to impaired HR repair by downregulating BRCA1 and RAD51, thus exacerbating DNA damage.
- SJNP releases cinnamaldehyde (CA), which amplifies intracellular ROS levels and induces mitochondrial dysfunction.
- SJNP demonstrated significant efficacy against murine triple-negative breast cancer (TNBC) with minimal observed toxicity.
Conclusions:
- The developed SJNP nanostructure offers a dual-action therapeutic approach, targeting both DNA repair pathways and mitochondrial function.
- SJNP shows promise as an effective and safe therapeutic strategy for triple-negative breast cancer treatment.
- This nano-strategy represents a significant advancement in overcoming drug resistance in cancer therapy.
