A pH-sensitive nanococktail enabled cancer stem cell elimination, deep tumour penetration, and tumour shrinkage

Le résumé fourni par la source

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 (CD44 high HCC1954 and CD44 low 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.

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