PLGA-based biocompatible nanoparticles improved anti-breast tumor efficacy of 1,25(OH)2D3 through the SOCS3/STAT3/EMT signaling axis

Abstract

Several studies have demonstrated that active vitamin D (1,25(OH)₂D₃) can impede the cancerous traits of breast cancer. However, due to the susceptibility of 1,25(OH)₂D₃ to degradation in the tumor microenvironment, higher doses were required to sustain its efficacy. This elevated dosage could lead to significant side effects, thereby constraining its practical application in clinical settings. The FDA-approved nanomaterial poly (lactic-co-glycolic acid) (PLGA) had the potential for utilization in clinical settings. It could be employed to helps in maintaining and extending the biological activity of the drugs, thereby enhancing their therapeutic efficacy. Hence, the potential of PLGA encapsulation to augment the anti-breast cancer properties of 1,25(OH)₂D₃ and the underlying mechanism remain uncertain. In this study, our findings not only demonstrated the effective encapsulation of 1,25(OH)₂D₃ in PLGA (PLGA-1,25(OH)₂D₃, PD) but also indicated that the PD has a more potent inhibitory effect on the proliferation and migration of breast cancer cells compared with 1,25(OH)₂D₃ alone. Consistently, PD exhibits superior efficacy in suppressing subcutaneous neoplasia and lung metastasis of breast cancer cells compared to 1,25(OH)₂D₃. It is noteworthy that PD significantly alleviates the adverse effects of increased serum calcium levels and weight loss in mice induced by 1,25(OH)₂D₃. Subsequently, bioinformatics analysis and western blot confirmed that PD showed a more pronounced upregulation of SOCS3 and a concurrent downregulation of JAK/STAT3 and PI3K/AKT signals compared to 1,25(OH)₂D₃ both in vivo and in vitro. Considering that epithelial-mesenchymal transition (EMT) is downstream of the SOCS3/STAT3/PI3K pathway, our findings also revealed that 1,25(OH)₂D₃ markedly regulated the expression of EMT markers. Additionally, the inhibitor of STAT3 exhibited inhibitory effects on EMT progression in breast cancer cells. Moreover, we manifested that PD robustly curtailed the EMT markers compared to 1,25(OH)₂D₃ in vivo. In conclusion, these findings elucidate PLGA-1,25(OH)₂D₃ enhances 1,25(OH)₂D₃'s antitumor effects through the SOCS3/STAT3/EMT signaling axis, offering potential targets for therapeutic interventions in breast cancer treatment.