A Neutrophil-Biomimic Platform for Eradicating Metastatic Breast Cancer Stem-like Cells by Redox Microenvironment Modulation and Hypoxia-Triggered Differentiation Therapy
We developed a neutrophil-biomimic platform that regulates redox balance and hypoxic-triggered differentiation to kill metastatic breast cancer stem cells in tumor hypoxia microenvironment. The related work was published online in Acta Pharmaceutica Sinica B under the theme of “A Neutrophil-Biomimic Platform for Eradicating Metastatic Breast Cancer Stem-like Cells by Redox Microenvironment Modulation and Hypoxia-Triggered Differentiation Therapy”.
Currently, despite recent advances in surgery and radiotherapy, chemotherapy remains the preferred treatment for metastatic triple negative breast cancer (TNBC) patients. Unfortunately, these strategies do not effectively increase the survival rate of patients due to the poor drug accumulation at the metastatic loci. Moreover, the tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Therefore, it might be a more reliable strategy for increasing the chemotherapy sensitivity by promoting BCSCs differentiation and simultaneously modulate the redox microenvironment for preventing non-BCSCs retro-differentiation.
In this work, we developed a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability and anchored chemotherapeutic doxorubicin (DOX) and BCSCs-differentiating all-trans retinoic acid (ATRA) with nitroimidazole to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core assembled from a nitroaromatics-derived block polymer. The platform can actively target the lung metastasis sites of TNBC, and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, ATRA could differentiate BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties on the polymer and prodrugs could modulate the tumor microenvironment by depleting NADPH to modulate redox microenvironment and further prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhanced chemotherapeutic cytotoxicity and eventually satisfies the demand for facilitating a maximized synergistic anti-metastasis efficacy.
Yongchao Chu is the first author of this paper, and Prof. Jiang Chen and Sun Tao are the corresponding authors of this paper. This work was supported by the National Natural Science Foundation of China and Program of Shanghai Academic Research Leader.
For more information: https://doi.org/10.1016/j.apsb.2022.05.027
