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A pH-sensitive imidazole grafted polymeric micelles nanoplatform based on ROS amplification for ferroptosis-enhanced
Zhuangzhuang Zhang1, Lingyang Wang2, Zhaoyuan Guo3
1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China; Ningbo Baoting Bioscience & Technology Co., Ltd, Ningbo 315100, China.
Abstract:
Highly toxic reactive oxygen species (ROS), crucial in inducing apoptosis and ferroptosis, are pivotal for cell death pathways in cancer therapy. However, the effectiveness of ROS-related tumor therapy is impeded by the limited intracellular ROS and substrates, coupled with the presence of abundant ROS scavengers like glutathione (GSH). In this research, we developed acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating a mitochondrial-targeting drug alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment. The imidazole grafted micelles exhibit prolonged blood circulation and improve the delivery efficiency of the hydrophobic drug α-TOS. Additionally, PPA's design aids in delivering Fe3+, supplying ample iron ions for chemodynamic therapy (CDT) and ferroptosis through the attachment of imidazole groups to Fe3+. In the tumor's weakly acidic intracellular environment, PPA/TF facilitates pH-responsive drug release. α-TOS specifically targets mitochondria, generating ROS and replenishing those depleted by the Fenton reaction. Moreover, the presence of Fe3+ in PPA/TF amplifies ROS upregulation, promotes GSH depletion, and induces oxidative damage and ferroptosis, effectively inhibiting tumor growth. This research presents an innovative ROS-triggered amplification platform that optimizes CDT and ferroptosis for effective cancer treatment.
Insights
This study introduces novel nanoparticles that enhance cancer therapy by increasing reactive oxygen species (ROS) and promoting ferroptosis. The developed system effectively targets tumors, leading to significant growth inhibition.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Reactive oxygen species (ROS) are critical for apoptosis and ferroptosis in cancer therapy.
- Limited intracellular ROS and abundant scavengers like glutathione (GSH) hinder ROS-related tumor therapy effectiveness.
Purpose of the Study:
- To develop acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment.
- To overcome limitations of ROS-related cancer therapy by amplifying ROS generation and promoting ferroptosis.
Main Methods:
- Development of imidazole-grafted micelles (PPA/TF) for improved drug delivery and prolonged circulation.
- Encapsulation of mitochondrial-targeting drug α-TOS within the nanoparticles.
- Utilizing Fe3+ for chemodynamic therapy (CDT) and ferroptosis induction, triggered by the tumor's acidic environment.
Main Results:
- PPA/TF nanoparticles demonstrated efficient delivery of α-TOS to mitochondria.
- The system amplified ROS production and promoted glutathione (GSH) depletion.
- Significant inhibition of tumor growth was observed due to induced oxidative damage and ferroptosis.
Conclusions:
- The developed PPA/TF nanoparticles represent an innovative ROS-triggered amplification platform.
- This platform effectively optimizes chemodynamic therapy (CDT) and ferroptosis for enhanced cancer treatment.
- The study highlights a promising strategy for overcoming ROS-related therapy limitations in oncology.
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