Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma
Authors Gong K, Dong Y, Wang L, Duan Y, Yu J, Sun Y, Bai M, Duan Y
Received 7 February 2020
Accepted for publication 10 June 2020
Published 4 August 2020 Volume 2020:15 Pages 5561—5571
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Mian Wang
Ke Gong,1 Yang Dong,1 Liting Wang,1 Yi Duan,2 Jian Yu,1 Ying Sun,1 Min Bai,3 Yourong Duan1
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, People’s Republic of China; 2Department of Clinical Medicine, North Sichuan Medical College, Sichuan 637100, People’s Republic of China; 3Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China
Correspondence: Yourong Duan
State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute, Renji Hospital School of Medicine, Shanghai Jiao Tong University, 2200/25 Xietu Road, Shanghai 200032, People’s Republic of China
Tel/ Fax +86-021-64437139
Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, People’s Republic of China
Tel/ Fax +86-13917045725
Purpose: Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed.
Methods: In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR.
Results: We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and − 9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels.
Conclusion: We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.
Keywords: cisplatin, chemotherapy, antagonist of S1PR1, pH sensitivity, nanoparticles