One-stone-two-birds Nano-cocktail Enables Cancer Cells/Stem Cells Dual Depletion and Efficacy/Toxicity Benefit Maximization in Breast Cancer Therapy

crossref(2024)

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摘要
Abstract Background: Cancer stem cells (CSCs) are recognized as the culprits of chemoresistance, tumor metastasis and relapse. Conventional chemotherapeutic drugs not only fail to effectively kill CSCs, but induce the acquisition of stemness characteristics in non-stem cancer cells. Meanwhile, most anti-CSCs drugs display marginal inhibitory effects on cancer cell proliferation. Therefore, developing a cancer cells/CSCs double-killing modality is highly desired. Methods: A carrier-free nano-cocktail is developed through precise co-assembly of a redox-responsive dimeric prodrug of docetaxel (DTX) and salinomycin (SAL, an anti-CSCs drug) for breast cancer treatment. In this study, we systematically investigated the co-assembly mechanism, reduction-responsive drug release behavior, cellular uptake efficiency, synergistic cytotoxicity, and anti-CSCs efficacy of the nano-cocktail through in vitro experiments. Additionally, the pharmacokinetics, biodistribution and synergistic anti-tumor/CSCs activity were explored in vivo. Results: Precision combination of DTX and SAL not only shows synergistic tumor killing activity, but also sharply reduces the proportion of CSCs in tumors. More importantly, tumor-specific prodrug activation-initiated drug release confers high drug co-delivery efficiency and low off-target toxicity risk to the nano-cocktail. As expected, such a one-stone-two-birds nanomedicine has excellent performance on tumor stemness depletion, antitumor responses, and treatment safety in a breast cancer mouse xenograft model. Conclusion: This study advances cancer cells/CSCs double-killing nanotherapeutics towards clinical breast cancer therapy.
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