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Intraoperative Cavity Local Delivery System with NETs-Specific Drug Release for Post-Breast Cancer Surgery Recurrence
Wan-Fang Zhu1,2, Wen-Jing Ji1, Qiu-Yuan Wang1
1Department of Pharmceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
Abstract:
Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors-β (TGF-β) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio-safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF-β at tumor-resection sites, whose unique mechanism for local TGF-β amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti-TGF-β. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF-β and related indicators, impeding epithelial-mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.
Insights
This study developed a novel hydrogel that mimics neutrophil extracellular traps (NETs) to combat breast cancer recurrence. The hydrogel delivers anti-transforming growth factor-beta (TGF-β) therapy, effectively inhibiting tumor relapse post-surgery.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Drug Delivery Systems
Background:
- Postoperative breast cancer recurrence presents limited therapeutic options.
- Transforming growth factor-beta (TGF-β) drives tumor recurrence, but conventional blocking strategies are insufficient.
- Neutrophil extracellular traps (NETs) amplify local TGF-β at tumor sites, increasing recurrence risk.
Purpose of the Study:
- To engineer a hydrogel system that mimics NETs formation for localized drug delivery.
- To investigate the hydrogel's ability to inhibit postoperative breast cancer recurrence by targeting TGF-β.
Main Methods:
- Fabrication of a hydrogel based on histidine (His) and sodium alginate (Alg) electrostatic interactions.
- Incorporation of arginine deiminase 4 (PAD4) for NETs mimicry and controlled release of anti-TGF-β therapy.
- In vivo evaluation of the hydrogel's efficacy in suppressing breast cancer recurrence and modulating the tumor microenvironment.
Main Results:
- The hydrogel successfully mimics NETs formation, enabling specific and sustained release of anti-TGF-β at targeted sites.
- Demonstrated superior inhibition of breast cancer recurrence by suppressing TGF-β, impeding epithelial-mesenchymal transition (EMT), and rectifying the immunosuppressive microenvironment.
- The system exhibited excellent biocompatibility and prolonged therapeutic effects.
Conclusions:
- A novel NETs-mimicking hydrogel offers a promising strategy for localized drug delivery to prevent postoperative breast cancer recurrence.
- This approach effectively targets the TGF-β pathway and modulates the tumor microenvironment for enhanced therapeutic outcomes.
- The developed hydrogel system provides a new paradigm for addressing challenges in postoperative cancer recurrence management.
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