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Redox-triggered activation of nanocarriers for mitochondria-targeting cancer chemotherapy
Wei Zhou1, Hui Yu, Liu-Jie Zhang
1Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China. swhuang@whu.edu.cn.
Abstract:
The importance of mitochondrial delivery of an anticancer drug to cancer cells has been recognized to improve therapeutic efficacy. The introduction of lipophilic cations, such as triphenylphosphonium (TPP), onto the surface of nanocarriers was utilized to target mitochondria via strong electrostatic interactions between positively charged TPP and the negatively charged mitochondrial membrane. However, the highly positive charge nature of TPP leads to rapid clearance from the blood, decrease of circulation lifetime, and nonspecific targeting of mitochondria of cells. Here, we report a strategy for improving the anticancer efficacy of paclitaxel via redox triggered intracellular activation of mitochondria-targeting. The lipid-polymer hybrid nanoparticles (LPNPs) are composed of poly(d,l-lactide-co-glycolide) (PLGA), a TPP-containing amphiphilic polymer (C18-PEG2000-TPP) and a reduction-responsive amphiphilic polymer (DLPE-S-S-mPEG4000). The charges of TPP in LPNPs were almost completely shielded by surface coating of a PEG4000 layer, ensuring high tumor accumulation. After uptake by cancer cells, the surface charges of LPNPs were recovered due to the detachment of PEG4000 under intracellular reductive conditions, resulting in rapid and precise localization in mitochondria. This kind of simple, easy and practicable mitochondria-targeting nanoplatform showed high anticancer activity, and the activatable strategy is valuable for developing a variety of nanocarriers for application in the delivery of other drugs.
Insights
This study developed novel lipid-polymer hybrid nanoparticles for improved anticancer drug delivery. These nanoparticles shield mitochondria-targeting charges until inside cancer cells, enhancing efficacy and reducing side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Mitochondrial drug delivery enhances anticancer efficacy.
- Triphenylphosphonium (TPP) targets mitochondria but causes rapid blood clearance and nonspecific targeting.
- A strategy is needed to overcome TPP limitations for effective cancer therapy.
Purpose of the Study:
- To develop a redox-triggered, mitochondria-targeting nanoplatform for improved paclitaxel delivery.
- To overcome the limitations of traditional TPP-based mitochondria targeting.
- To enhance anticancer efficacy and reduce off-target effects.
Main Methods:
- Fabrication of lipid-polymer hybrid nanoparticles (LPNPs) using PLGA, C18-PEG2000-TPP, and DLPE-S-S-mPEG4000.
- Shielding of TPP charges with a PEG4000 layer for prolonged circulation and tumor accumulation.
- Redox-triggered detachment of PEG4000 within cancer cells to expose TPP for mitochondria localization.
Main Results:
- LPNPs demonstrated shielded positive charges, ensuring high tumor accumulation.
- Intracellular reductive conditions triggered PEG4000 detachment, recovering TPP charges.
- Recovered charges facilitated rapid and precise localization of LPNPs within cancer cell mitochondria.
- The nanoplatform exhibited significant anticancer activity.
Conclusions:
- The developed nanoplatform offers a simple, effective strategy for mitochondria-targeted drug delivery.
- Redox-triggered charge recovery overcomes limitations of traditional TPP targeting.
- This activatable nanoplatform shows promise for enhancing anticancer efficacy and developing new drug delivery systems.
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