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A ferroptosis-based intelligent nanoplatform with chemo-sonodynamic therapy carrying oxygen for improving tumor
Weilin Wang1, Qiaoying Hu1, Chunyan Wu1
1Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China.
Abstract:
Ferroptosis and sonodynamic therapy (SDT) have both been recognized as powerful weapons in cancer treatment, especially in non-small-cell lung carcinoma (NSCLC) recently. However, the lack of effective sono-sensitizer and ferroptosis regulator limited their usage. In order to overcome the limitation, a novel nanoplatform of DTX-CS/ART/PFCA@RGD (cRCAPD) was fabricated based on SDT and ferroptosis. Nanoparticles, under the action of c(RGDfk) cyclic peptides and their skeleton chondroitin sulfate (CS), could specifically target αvβ3 and CD44 receptors, respectively, thereby targeting tumor sites. Meanwhile, the peroxy-bridge structure of ART disrupted the intracellular iron homeostasis while generating highly toxic reactive oxygen species (ROS) under the SDT. Docetaxel (DTX) in nanoparticles led to the excellent apoptosis of A549 cells. Oxygen carried by PFCA alleviated the tumor hypoxic microenvironment, downregulated HIF-1α, and provided substrates for SDT. Further, the nanoparticles showed a strong immunogenic cell death (ICD) effect, modulating the number of T cells and dendritic cells in tumor-bearing mice. In summary, the proposed therapeutic strategy based on SDT and ferroptosis holds promising potential for synergistic treatment of lung cancer in future clinical applications.
Insights
This study introduces a novel nanoplatform for synergistic lung cancer treatment, combining sonodynamic therapy (SDT) and ferroptosis. The approach enhances tumor targeting and overcomes limitations in current cancer therapies.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Ferroptosis and sonodynamic therapy (SDT) show promise for treating non-small-cell lung carcinoma (NSCLC).
- Limitations include the lack of effective sono-sensitizers and ferroptosis regulators.
- Targeted drug delivery systems are needed to improve efficacy and overcome treatment resistance.
Purpose of the Study:
- To develop a novel nanoplatform (cRCAPD) integrating SDT and ferroptosis for enhanced NSCLC treatment.
- To investigate the targeted delivery and therapeutic mechanisms of the nanoplatform.
- To evaluate the synergistic effects of SDT and ferroptosis induction in a preclinical lung cancer model.
Main Methods:
- Fabrication of a novel nanoplatform (DTX-CS/ART/PFCA@RGD) incorporating docetaxel (DTX), chondroitin sulfate (CS), artemisinin (ART), perfluorochemicals (PFCA), and cyclic (RGDfk) peptides.
- Utilizing targeting moieties (c(RGDfk) and CS) for specific accumulation at tumor sites via αvβ3 and CD44 receptors.
- Investigating the disruption of iron homeostasis and generation of reactive oxygen species (ROS) by ART under SDT.
- Assessing the role of PFCA in alleviating tumor hypoxia and providing substrates for SDT.
- Evaluating the anti-cancer efficacy, apoptosis induction, and immunogenic cell death (ICD) effects in A549 cells and tumor-bearing mice.
Main Results:
- The cRCAPD nanoplatform demonstrated targeted delivery to tumor sites.
- Artemisinin effectively disrupted intracellular iron homeostasis and generated ROS under SDT, inducing ferroptosis.
- Docetaxel promoted apoptosis in A549 cells.
- PFCA mitigated tumor hypoxia, downregulated HIF-1α, and supported SDT.
- The nanoplatform induced significant ICD, modulating T cell and dendritic cell populations in vivo.
Conclusions:
- The developed nanoplatform (cRCAPD) offers a promising strategy for synergistic NSCLC treatment by combining SDT and ferroptosis.
- This approach effectively targets tumors, enhances therapeutic effects through ROS generation and apoptosis induction, and modulates the tumor immune microenvironment.
- The findings suggest significant potential for clinical translation in lung cancer therapy.
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