Abstract
Metformin (MET) is an anti-diabetic drug effective against breast cancer, targeting breast cancer stem cells (BCSCs). MET-encapsulating liposome (LP-MET) and Herceptin-conjugated LP-MET (Her-LP-MET) were evaluated for their anti-cancer effect in vitro and in vivo. Size and zeta potentials of LP-MET and Her-LP-MET were suitable for enhanced permeability and retention effects. Her-LP-MET yielded greater inhibition of BCSC proliferation in vitro than free MET or LP-MET, as well as a dose-dependent long-term anti-proliferation effect. Further, the anti-migration effect of Her-LP-MET on BCSCs was superior to that of MET or LP-MET, and was enhanced when used in concert with doxorubicin (DOX). In a mouse model, Her-LP-MET combined with free DOX was more effective than free MET, free DOX, or Her-LP-MET. Moreover, Her-LP-MET combined with free DOX yielded tumor remission, whereas free DOX alone resulted in metastasis or death. As such, Her-LP-MET formulation is expected to provide a new therapeutic modality targeting BCSCs.
Highlights
Breast cancer is a common type of female cancer, constituting the second leading cause of death for women
Recent studies have demonstrated that low-dose MET can affect breast cancer by targeting Breast Cancer Stem Cells (BCSCs) [17,18,19,20] MET is limited by low bioavailability due to its short half-life, high hydrophilicity, and non-selective biodistribution [21]
We investigated the direct inhibition of growth of breast cancer cells after binding of Herceptin and differentiation of BCSCs into breast cancer cells by MET, followed by the killing of these cells with doxorubicin (DOX)
Summary
Breast cancer is a common type of female cancer, constituting the second leading cause of death for women. CSCs can regenerate various cancer cell types during radiation therapy and chemotherapy, resulting in relapse [5,6]. Diabetes patients treated with MET have been shown to have a reduced cancer risk, it is unclear whether MET affects cancer directly or indirectly [11,12,13,14,15]. MET has become an object of research focus due to its ability to target CSCs, which affect chemoresistance, cell proliferation, self-renewal, differentiation, metastasis, metabolism, and tumor relapse [16]. Recent studies have demonstrated that low-dose MET can affect breast cancer by targeting BCSCs [17,18,19,20] MET is limited by low bioavailability due to its short half-life, high hydrophilicity, and non-selective biodistribution [21]. An improved understanding of MET’s anti-cancer mechanism will help to optimize its treatment conditions as a monotherapy or in combination with other cancer treatment strategies
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