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Published on: May 14, 2021
Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness
Xi Chen1, Yadi Fan2, Jinghua Sun2
1The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, Guangdong 518053, China; Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China.
Abstract:
As the driving force of tumor progression, cancer stem cells (CSCs) hold much lower cellular stiffness than bulk tumor cells across many cancer types. However, it remains unclear whether low cell stiffness can be harnessed in nanoparticle-based therapeutics for CSC targeting. We report that breast CSCs exhibit much lower stiffness but considerably higher uptake of nitrogen-doped graphene quantum dots (N-GQDs) than bulk tumor cells. Softening/stiffening cells enhances/suppresses nanoparticle uptake through activating/inhibiting clathrin- and caveolae-mediated endocytosis, suggesting that low cell stiffness mediates the elevated uptake in soft CSCs that may lead to the specific elimination. Further, soft CSCs enhance drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs by reducing intracellular pH and exocytosis. Remarkably, drug-loaded N-GQDs specifically eliminate soft CSCs both in vitro and in vivo, inhibit tumor but not animal growth, and reduce the tumorigenicity of xenograft cells. Our findings unveil a new mechanism by which low cellular stiffness can be harnessed in nanoparticle-based strategies for specific CSC elimination, opening a new paradigm of cancer mechanomedicine. STATEMENT OF SIGNIFICANCE: Low cell stiffness is associated with high malignancy of tumor cells and thus serves as a mechanical hallmark of CSCs. However, it remains unclear whether cellular stiffness can be exploited for specific targeting of soft CSCs. This work reports that soft CSCs exhibit high N-GQD uptake compared to stiff tumor cells, which is regulated by cellular stiffness. Further, soft CSCs have enhanced drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs, which enable the specific elimination of malignant CSCs both in vitro and in vivo with minimal side effect. In summary, our study demonstrates that CSC's low stiffness can be harnessed as a mechanical target for specific eradication, which provides a new paradigm of cancer mechanomedicine.
Insights
Cancer stem cells (CSCs) are softer and absorb more nanoparticles. This study shows that targeting this low cellular stiffness with drug-loaded nanoparticles can specifically eliminate CSCs, offering a new approach in cancer mechanomedicine.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Nanotechnology
Background:
- Cancer stem cells (CSCs) drive tumor progression and exhibit lower cellular stiffness than bulk tumor cells.
- Exploiting the mechanical properties of CSCs for targeted therapy remains an underexplored area.
- Nanoparticle uptake is influenced by cellular mechanical properties, but its specific application to CSC targeting is unclear.
Purpose of the Study:
- To investigate if low cellular stiffness can be utilized for nanoparticle-based targeting of cancer stem cells (CSCs).
- To explore the mechanism by which cellular stiffness influences nanoparticle uptake and therapeutic efficacy in CSCs.
- To demonstrate the potential of harnessing cellular stiffness for developing novel cancer mechanomedicine strategies.
Main Methods:
- Utilized nitrogen-doped graphene quantum dots (N-GQDs) to assess uptake in breast CSCs versus bulk tumor cells.
- Manipulated cellular stiffness (softening/stiffening) to evaluate its impact on nanoparticle endocytosis pathways (clathrin- and caveolae-mediated).
- Investigated the effect of soft CSCs on drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs.
- Assessed the efficacy of drug-loaded N-GQDs in specifically eliminating CSCs in vitro and in vivo, and their impact on tumor growth and tumorigenicity.
Main Results:
- Breast CSCs showed significantly lower stiffness and higher N-GQD uptake compared to bulk tumor cells.
- Cellular softening enhanced nanoparticle uptake by activating endocytosis, while stiffening suppressed it.
- Soft CSCs demonstrated enhanced drug release, retention, and nuclear accumulation of drug-loaded N-GQDs due to reduced intracellular pH and exocytosis.
- Drug-loaded N-GQDs specifically eliminated CSCs in vitro and in vivo, inhibited tumor growth, and reduced xenograft cell tumorigenicity.
Conclusions:
- Low cellular stiffness is a key factor mediating enhanced nanoparticle uptake in CSCs.
- Harnessing cellular stiffness through nanoparticle-based strategies offers a promising approach for specific CSC elimination.
- This study establishes a new paradigm in cancer mechanomedicine by targeting the mechanical properties of CSCs for therapeutic benefit.
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