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Tumor microenvironment-initiated lipid redox cycling for efficient triple-negative breast cancer therapy
Tian-Jiao Zhou1, Xing Wan1, Meng-Meng Zhang1
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China.
Abstract:
The use of overwhelming reactive oxygen species (ROS) attack has shown great potential for treating aggressive malignancies; however, targeting this process for further applications is greatly hindered by inefficiency and low selectivity. Here, a novel strategy for ROS explosion induced by tumor microenvironment-initiated lipid redox cycling was proposed, which was developed by using soybean phosphatidylcholine (SPC) to encapsulate lactate oxidase (LOX) and sorafenib (SRF) self-assembled nanoparticles (NPs), named LOX/SRF@Lip. SPC is not only the delivery carrier but an unsaturated lipid supplement for ROS explosion. And LOX catalyzes excessive intratumoral lactate to promote the accumulation of large amounts of H2O2. Then, H2O2 reacts with excessive endogenous iron ions to generate amounts of hydroxyl radical for the initiation of SPC peroxidation. Once started, the reaction will proceed via propagation to form new lipid peroxides (LPO), resulting to devastating LPO explosion and widespread oxidative damage in tumor cells. Furthermore, SRF makes contribution to mass LPO accumulation by inhibiting LPO elimination. Compared to normal tissue, tumor tissue has higher levels of lactate and iron ions. Therefore, LOX/SRF@Lip shows low toxicity in normal tissues, but generates efficient inhibition on tumor proliferation and metastasis, enabling excellent and safe tumor-specific therapy. This work offers new ideas on how to magnify anticancer effect of ROS through rational nanosystem design and tumor-specific microenvironment utilization.
Insights
This study introduces a novel nanoparticle strategy that utilizes the tumor microenvironment to generate a powerful reactive oxygen species (ROS) explosion, effectively targeting and destroying cancer cells with high selectivity and minimal harm to healthy tissues.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Reactive oxygen species (ROS) show promise for cancer treatment but suffer from inefficiency and low selectivity.
- Targeting ROS generation within the tumor microenvironment is a key challenge in developing effective cancer therapies.
Purpose of the Study:
- To develop a novel nanosystem for enhanced ROS generation and tumor-specific cancer therapy.
- To leverage the unique tumor microenvironment for amplified oxidative damage and improved therapeutic outcomes.
Main Methods:
- Soybean phosphatidylcholine (SPC) encapsulated nanoparticles (LOX/SRF@Lip) containing lactate oxidase (LOX) and sorafenib (SRF) were synthesized.
- LOX catalyzes lactate to produce hydrogen peroxide (H2O2), which reacts with iron ions to initiate SPC peroxidation.
- SRF inhibits lipid peroxide elimination, leading to a cascade of lipid peroxidation (LPO) and ROS explosion within tumor cells.
Main Results:
- The LOX/SRF@Lip nanoparticles effectively induced ROS explosion and lipid peroxide accumulation specifically in tumor cells.
- The system demonstrated high selectivity, with significantly lower toxicity in normal tissues compared to tumor tissues.
- Significant inhibition of tumor proliferation and metastasis was observed, indicating potent anticancer efficacy.
Conclusions:
- This novel nanosystem effectively utilizes the tumor microenvironment to amplify ROS-induced oxidative damage for targeted cancer therapy.
- The strategy offers a promising approach to overcome the limitations of ROS-based cancer treatments through rational nanosystem design.
- The developed LOX/SRF@Lip nanoparticles present a safe and effective platform for tumor-specific therapy by exploiting tumor-specific metabolic characteristics.
