Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.
Highlights
Breast cancer is the most common cancer among women and the second leading cause of cancer-related death in women[1]
We showed that paclitaxel and combretastatin A4 (CA4) inhibited the viability of bulk Triple-negative breast cancer (TNBC) cells, while enriching cancer stem cells (CSCs) and upregulating oncogenic Yes-associated protein (YAP) signal, both of which can be effectively counteracted by verteporfin
Triple drug-NPs in combination was able to suppress the YAP target genes upregulated by paclitaxel-NP and CA4-NP (Fig. 2C, D). These results suggest that suppression of YAP signal by verteporfin-NP in the triple drug-NP combination may contribute to the CSC inhibition as shown in Fig. 1 and Fig. S4
Summary
Breast cancer is the most common cancer among women and the second leading cause of cancer-related death in women[1]. We showed that paclitaxel and CA4 inhibited the viability of bulk TNBC cells, while enriching CSCs and upregulating oncogenic YAP signal, both of which can be effectively counteracted by verteporfin.
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