Related Experiment Video
Updated: Aug 17, 2026
Using In Vitro Live-cell Imaging to Explore Chemotherapeutics Delivered by Lipid-based Nanoparticles
Published on: November 1, 2017
Lipid Nanoparticular Codelivery System for Enhanced Antitumor Effects by Ferroptosis-Apoptosis Synergistic with
Weiran Cao1, Xue Zhang1, Yaxuan Feng1
1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China.
Abstract:
Intrinsic or acquired resistance to chemical drugs severely limits their therapeutic efficacy in cancer treatment. Various intracellular antioxidant molecules, particularly glutathione (GSH), play a crucial role in maintaining intracellular redox homeostasis by mitigating the overproduced reactive oxygen species (ROS) due to rapid cell proliferation. Notably, these antioxidants also eliminate chemical-drug-induced ROS, eventually diminishing their cytotoxicity and rendering them less effective. In this study, we combined erastin, a GSH biosynthesis inhibitor, with 2'-deoxy-5-fluorouridine 5'-monophosphate sodium salt (FdUMP), an ROS-based drug, to effectively disrupt intracellular redox homeostasis and reverse chemotherapy resistance. Therefore, efficient ferroptosis and apoptosis were simultaneously induced for enhanced antitumor effects. Additionally, we employed small interfering RNA targeting PD-L1 (siPD-L1) as a third agent to block immune-checkpoint recognition by CD8+ T cells. The highly immunogenic cell peroxidates or damage-associated molecular patterns (DAMPs) induced by erastin acted synergistically with downregulated PD-L1 to enhance the antitumor effects. To codeliver these three drugs simultaneously and efficiently, we designed GE11 peptide-modified lipid nanoparticles (LNPs) containing calcium phosphate cores to achieve high encapsulation efficiencies. In vitro studies verified its enhanced cytotoxicity, efficient intracellular ROS induction and GSH/GPX4 downregulation, substantial lipid peroxidation product accumulation, and mitochondrial depolarization. In vivo, this formulation effectively accumulated at tumor sites and achieved significant tumor inhibition in subcutaneous colon cancer (CRC) mouse models with a maximum tumor inhibition rate of 83.89% at a relatively low dose. Overall, a strategy to overcome clinical drug resistance was verified in this study by depleting GSH and activating adaptive immunity.
Insights
This study combines a glutathione inhibitor and chemotherapy drug with an immunotherapy agent to overcome cancer drug resistance. The novel nanoparticle delivery system effectively reduced tumor growth by inducing ferroptosis, apoptosis, and enhancing adaptive immunity.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Nanomedicine
Background:
- Drug resistance limits cancer therapy efficacy, partly due to antioxidants like glutathione (GSH) neutralizing chemotherapy-induced reactive oxygen species (ROS).
- Overcoming this resistance requires strategies to disrupt intracellular redox homeostasis and enhance drug-induced cell death.
- Combining chemotherapy with immune-modulating agents can improve antitumor responses.
Purpose of the Study:
- To develop a multi-drug nanoparticle system to overcome chemotherapy resistance in cancer.
- To simultaneously induce ferroptosis and apoptosis while enhancing anti-tumor immunity.
- To investigate the synergistic effects of a GSH inhibitor, ROS-based drug, and PD-L1 blockade.
Main Methods:
- Co-delivery of erastin (GSH inhibitor), FdUMP (ROS-based drug), and siPD-L1 using GE11 peptide-modified lipid nanoparticles (LNPs) with calcium phosphate cores.
- In vitro evaluation of cytotoxicity, ROS induction, GSH/GPX4 downregulation, lipid peroxidation, and mitochondrial depolarization.
- In vivo assessment of tumor inhibition in subcutaneous colon cancer (CRC) mouse models.
Main Results:
- The LNP formulation demonstrated enhanced cytotoxicity and effectively disrupted redox homeostasis.
- Simultaneous induction of ferroptosis and apoptosis was observed, leading to significant lipid peroxidation and mitochondrial damage.
- In vivo studies showed substantial tumor inhibition (up to 83.89%) in CRC models with effective tumor accumulation.
Conclusions:
- The developed nanoparticle system successfully overcomes drug resistance by depleting GSH and inducing cell death.
- Combined therapy with PD-L1 blockade synergistically enhances antitumor effects by activating adaptive immunity.
- This strategy offers a promising approach for improving cancer treatment efficacy.
Related Concept Videos
02:26Protein Networks
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
01:30Apoptosis
01:17Phagocytosis of Apoptotic Cells
Normal cells contain receptors that prevent them from being recognized by phagocytes.
01:11Cellular Injury IlI: Cellular Death