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Published on: May 22, 2020
A pH-sensitive nanococktail enabled cancer stem cell elimination, deep tumour penetration, and tumour shrinkage
Kamel S Ahmed1, Emma Nolan2, Jingjing Wang3
1School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Abstract:
Cancer stem cells (CSCs) are intrinsically resistant to conventional therapies and play a pivotal role in cancer metastasis and recurrence. Eradication of CSCs requires combination strategies that simultaneously target multiple pathways at therapeutical concentrations throughout tumours. This study investigated the potential of a fusogenic pH-sensitive liposomal (pSL) nanococktail comprising doxorubicin and bufalin for targeting CSCs in clinically relevant HER2-positive breast cancer models, including cell lines (CD44high HCC1954 and CD44low BT474), homotypic and heterotypic spheroids, patient-derived organoids, and orthotopic HCC1954 mouse xenografts. At the optimal doxorubicin: bufalin ratio (10:1), the pSL-cocktail demonstrated pronounced synergistic efficacy and significantly outperformed all control formulations, including monodrug-loaded pSLs, non-pH-sensitive (DOXIL-like) liposomes, and free drugs. It significantly suppressed tumour proliferation and stemness, including CSC-associated migration, mammosphere formation, and self-renewal. In spheroids, the nanococktail rapidly penetrated to the spheroid core (≥100 µm within 1 h) and suppressed invasive dissemination. Similarly, it disrupted patient-derived organoids, achieving > 90% reduction in ATP levels and > 90% cell death. In vivo, the pSL-cocktail was well-tolerated and achieved significant tumour shrinkage, whereas DOXIL-like liposomes and free drugs showed minimal activity or severe adverse effects. Overall, this pSL-cocktail demonstrates strong potential for CSC-elimination and tumour clearance through synergistic drug combination, superior tumour penetration, and endosomal pH-triggered intracellular drug release.
Insights
This study developed a pH-sensitive liposomal nanococktail of doxorubicin and bufalin to target cancer stem cells (CSCs). The combination therapy showed significant efficacy in eliminating CSCs and reducing tumor growth in breast cancer models.
Area of Science:
- Nanomedicine
- Cancer Biology
- Pharmacology
Background:
- Cancer stem cells (CSCs) are resistant to conventional therapies, driving cancer metastasis and recurrence.
- Targeting CSCs requires combination strategies that address multiple pathways simultaneously.
- HER2-positive breast cancer presents a significant therapeutic challenge due to CSC resistance.
Purpose of the Study:
- To investigate a fusogenic pH-sensitive liposomal (pSL) nanococktail of doxorubicin and bufalin for targeting CSCs.
- To evaluate the efficacy of this nanococktail in preclinical models of HER2-positive breast cancer.
- To assess the drug delivery, synergistic effects, and safety profile of the pSL-cocktail.
Main Methods:
- Development of a pH-sensitive liposomal nanococktail with doxorubicin and bufalin at a 10:1 ratio.
- In vitro testing using breast cancer cell lines (CD44high/low), spheroids, and patient-derived organoids.
- In vivo evaluation in orthotopic HCC1954 mouse xenografts.
- Comparison with monodrug liposomes, non-pH-sensitive liposomes (DOXIL-like), and free drugs.
Main Results:
- The pSL-cocktail demonstrated significant synergistic efficacy, outperforming control formulations.
- It effectively suppressed tumor proliferation, stemness, migration, mammosphere formation, and self-renewal.
- Rapid penetration into spheroids (≥100 µm within 1h) and disruption of organoids (>90% cell death) were observed.
- In vivo studies showed significant tumor shrinkage with good tolerability, unlike other treatments.
Conclusions:
- The pSL-nanococktail exhibits strong potential for CSC elimination and tumor clearance.
- Synergistic drug combination, enhanced tumor penetration, and pH-triggered release contribute to its efficacy.
- This approach offers a promising strategy for overcoming therapeutic resistance in HER2-positive breast cancer.
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