Ke Gong1, Juyang Jiao2, Chaoqun Xu3, Yang Dong1, Dongxiao Li3, Di He1, Jian Yu1, Ying Sun1, Wei Zhang4, Min Bai5, Yourong Duan6. 1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. 2. Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China. 3. Sichuan Academy of Chinese Medicine Science, Chengdu, 610041, Sichuan, China. 4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. wzhang@shsci.org. 5. Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China. baimin101@126.com. 6. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. yrduan@shsci.org.
Abstract
BACKGROUND: 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). Hence, novel treatment strategy is urgently needed. RESULTS: We 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. CONCLUSIONS: Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.
BACKGROUND: 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). Hence, novel treatment strategy is urgently needed. RESULTS: We 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 humanbreast 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-231tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. CONCLUSIONS: Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.
Entities:
Keywords:
BAF312; P-STAT3; S1PR1; Targeted nanoparticle; Triple-negative breast cancer; VEGFA
Authors: Tanya Gritsko; Ann Williams; James Turkson; Satoshi Kaneko; Tammy Bowman; Mei Huang; Sangkil Nam; Ibrahim Eweis; Nils Diaz; Daniel Sullivan; Sean Yoder; Steve Enkemann; Steven Eschrich; Ji-Hyun Lee; Craig A Beam; Jin Cheng; Susan Minton; Carlos A Muro-Cacho; Richard Jove Journal: Clin Cancer Res Date: 2006-01-01 Impact factor: 12.531
Authors: Masayuki Nagahashi; Subramaniam Ramachandran; Eugene Y Kim; Jeremy C Allegood; Omar M Rashid; Akimitsu Yamada; Renping Zhao; Sheldon Milstien; Huiping Zhou; Sarah Spiegel; Kazuaki Takabe Journal: Cancer Res Date: 2012-02-01 Impact factor: 12.701
Authors: Eriko Katsuta; Li Yan; Masayuki Nagahashi; Ali Raza; Jamie L Sturgill; Debra E Lyon; Omar M Rashid; Nitai C Hait; Kazuaki Takabe Journal: J Surg Res Date: 2017-06-29 Impact factor: 2.192
Authors: Timothy C Johnstone; Nora Kulak; Eric M Pridgen; Omid C Farokhzad; Robert Langer; Stephen J Lippard Journal: ACS Nano Date: 2013-05-22 Impact factor: 15.881