Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.
Keywords: Cancer stem cells; Combination therapy; Drug delivery; Nanomedicine; Prodrug; Tumor mechanics.
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