Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth

AbstractTaxane efficacy in triple negative breast cancer (TNBC) is limited by insufficient tumor accumulation and severe off-target effects. Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug. Here, 1,000 nm × 400 nm discoidal polymeric nanoconstructs (DPN) encapsulating docetaxel (DTXL) and the near infrared compound lipid-Cy5 were engineered. DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol) template with a polymer mixture comprising poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) diacrylate (PEG-DA) chains together with therapeutic and imaging agents. The resulting “multi-passage” DPN exhibited higher DTXL loading, lipid-Cy5 stability, and stiffness as compared to the conventional “single-passage” approach. Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof. Empty DPN had no toxicity on TNBC cells, whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL (IC50 = 2.6 nM ± 1.0 nM vs. 7.0 nM ± 1.09 nM at 72 h). In orthotopic murine models, DPN accumulated in TNBC more efficiently than free-DTXL. With only 2 mg/kg DTXL, intravenously administered every 2 days for a total of 13 treatments, DTXL-DPN induced tumor regression and were associated to an overall 80% survival rate as opposed to a 30% survival rate for free-DTXL, at 120 days. All untreated mice succumbed before 90 days. Collectively, this data demonstrates that vascular confined multi-passage DPN, biomimicking the behavior of circulating platelets, can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.

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A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01800-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Wei Xie ◽

Huijie Zhao ◽

Fengxian Wang ◽

Yiyun Wang ◽

Yuan He ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Near Infrared ◽

Triple Negative ◽

Vasculogenic Mimicry ◽

Xenograft Model ◽

Luciferase Reporter ◽

Antitumor Effects ◽

Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

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