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A hyaluronic acid modified cuprous metal-organic complex for reversing multidrug resistance via redox dyshomeostasis
Yichen Wan1, Zelong Chen1, Yi Wang1
1College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
Abstract:
Multidrug resistance (MDR) which is often related to the overexpression of P-glycoprotein (P-gp) in drug-resistant cancer cells has been a major problem faced by current cancer chemotherapy. Reversing P-gp-related MDR by disrupting tumor redox homeostasis that regulates the expression of P-gp is a promising strategy. In this work, a hyaluronic acid (HA) modified nanoscale cuprous metal-organic complex (HA-CuTT) was developed to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis, which was achieved by both Cu+-catalyzed generation of •OH and disulfide bonds-mediated depletion of glutathione (GSH). In vitro studies reveal that the DOX-loaded complex (HA-CuTT@DOX) has excellent targeting ability to HepG2-ADR cells due to the modification of HA and effectively induces redox dyshomeostasis in HepG2-ADR cells. Moreover, HA-CuTT@DOX can cause mitochondrial damage, decrease ATP level, and downregulate the P-gp expression, thereby leading to the reversal of MDR and the increased drug accumulation in HepG2-ADR cells. Importantly, in vivo experimental results show that it can achieve effective inhibition (89.6 %) of tumor growth in nude mice bearing HepG2-ADR cells. This is the first work to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis based on a HA modified nanoscale cuprous metal-organic complex, providing a new therapeutic paradigm for effective treatment of MDR-related cancer.
Insights
This study introduces a novel hyaluronic acid-modified nanoscale cuprous metal-organic complex (HA-CuTT) to combat multidrug resistance (MDR) in cancer. The HA-CuTT@DOX effectively reverses P-glycoprotein (P-gp)-related MDR by disrupting tumor redox balance, enhancing chemotherapy efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) overexpression is a significant challenge in cancer chemotherapy.
- Disrupting tumor redox homeostasis offers a promising strategy to overcome P-gp-related MDR.
Purpose of the Study:
- To develop a hyaluronic acid (HA)-modified nanoscale cuprous metal-organic complex (HA-CuTT) for reversing P-gp-related MDR.
- To investigate the mechanism of HA-CuTT in inducing two-way regulated redox dyshomeostasis and its therapeutic effects.
Main Methods:
- Synthesis and characterization of HA-CuTT nanoparticles.
- Loading of doxorubicin (DOX) onto HA-CuTT (HA-CuTT@DOX).
- In vitro evaluation of cellular uptake, redox dyshomeostasis induction, mitochondrial damage, ATP depletion, P-gp downregulation, and drug accumulation in HepG2-ADR cells.
- In vivo tumor growth inhibition assessment in nude mice.
Main Results:
- HA-CuTT@DOX demonstrated enhanced targeting of HepG2-ADR cells and effectively induced redox dyshomeostasis.
- The complex caused mitochondrial damage, reduced ATP levels, and downregulated P-gp expression, reversing MDR and increasing intracellular drug accumulation.
- In vivo studies showed significant tumor growth inhibition (89.6%) in mice bearing HepG2-ADR tumors.
Conclusions:
- HA-CuTT@DOX successfully reverses P-gp-related MDR through a novel two-way redox dysregulation mechanism.
- This approach offers a new therapeutic strategy for treating multidrug-resistant cancers.
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