The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer

Ke Gong,Juyang Jiao,Di He,Yourong Duan,Ying Sun,Min Bai,Jian Yu,Wei Zhang,De Zhao,Chaoqun Xu,Yang Dong,Dongxiao Li

doi:10.1186/s12951-021-00904-6

Abstract

BackgroundOverexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed.ResultsWe found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and − 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis.ConclusionsOur data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.Graphic abstract

Highlights

Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC)
Analysis of the Oncomine database indicated that the sphingosine 1 phosphate receptor 1 (S1PR1) expression level was higher in breast cancer than in normal tissues (Fig. 1f ), which suggests that S1PR1 could be a novel target for breast cancer treatment
The TIMER database showed that S1PR1 and STAT3 had positive connections in breast cancer (Fig. 1j), and STAT3 and VEGFA were positively connected (Fig. 1k)

Summary

Introduction

Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Chen SH et al compared the immunohistochemical staining of vessel endothelial cells in normal organs and tumor tissues and found that more P-STAT3 was present in tumor tissues than in normal tissues [27] These results suggest that P-STAT3 regulates the expression of VEGFA and that downregulating the activation of STAT3 can be a potent strategy for inhibiting the overexpressed VEGFA. Research has reported that S1PR1 activity increases tumor growth by amplifying VEGFA angiogenic signaling [30] These studies suggested that S1PR1 positively affects the expression of VEGFA. We hypothesize that S1PR1 could serve as a potent antitumor and antiangiogenic target in breast cancer by downregulating the P-STAT3/VEGFA pathway

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Conclusion