Abstract
Standard chemotherapy cannot eradicate triple-negative breast cancer (TNBC) while the residual cancer cells readily form the vasculogenic mimicry (VM) channels, which lead to the relapse of cancer after treatment. In this study, the functional vincristine plus dasatinib liposomes, modified by a targeting molecule DSPE-PEG2000-c(RGDyK), were fabricated to address this issue. The investigations were performed on TNBC MDA-MB-231 cells and MDA-MB-231 xenografts in nude mice. The liposomes exhibited the superior performances in the following aspects: the enhancement of cellular uptake via targeted action; the induction of apoptosis via activation of caspase 8, 9, and 3, increased expression of Bax, decreased expression of Mcl-1, and generation of reactive oxygen species (ROS); and the deletion of VM channels via inhibitions on the VM channel indicators, which consisted of vascular endothelial-cadherin (VE-Cad), focal adhesion kinase (FAK), phosphatidylinositide 3-kinase (PI3K), and matrix metallopeptidases (MMP-2, and MMP-9). Furthermore, the liposomes displayed the prolonged circulation time in the blood, the increased accumulation in tumor tissue, and the improved therapeutic efficacy along with deletion of VM channels in the TNBC-bearing mice. In conclusion, the nanostructured functional drug-loaded liposomes may provide a promising strategy for the treatment of invasive TNBC along with deletion of VM channels.
Highlights
Breast cancer is the most common malignant disease and a major cause of mortality among women worldwide [1]
The results indicated that the average particle sizes of the liposomes were in the range of 100–107 nm with a narrow polydispersity index (PDI; ≤ 0.2), and the charge values were slightly negative (-6 mV)
Results demonstrated that the functional coumarin liposomes show a strong penetrating ability (Figure 7A), and the functional vincristine plus dasatinib liposomes exhibit a strong destructing efficacy (Figure 7B and 7C). These results indicated the roles of functional vincristine plus dasatinib liposomes in potentially treating refractory solid triple-negative breast cancer (TNBC) with a strong penetrating ability and a destructing efficacy
Summary
Breast cancer is the most common malignant disease and a major cause of mortality among women worldwide [1]. 1.4 million individuals are diagnosed with breast cancer globally, with more than 450,000 deaths per year [2]. Among these cases, approximately 15–20% are characterized as the triple-negative breast cancer (TNBC) phenotype, namely, the absence of estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 [3, 4]. The residual cancer cells readily proliferate via the formation of highly patterned VM channels, which provide nutrients to the relapsed cancer cells. The elimination of VM channels plays a crucial role in a successful treatment of TNBC
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