Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma.
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.
['Gong|Ke|K|', 'Dong|Yang|Y|', 'Wang|Liting|L|', 'Duan|Yi|Y|', 'Yu|Jian|J|', 'Sun|Ying|Y|', 'Bai|Min|M|', 'Duan|Yourong|Y|0000-0002-3781-7845']
D001384:Azetidines D001593:Benzyl Compounds D002130:Calcium Phosphates D045744:Cell Line, Tumor D002945:Cisplatin D016503:Drug Delivery Systems D019008:Drug Resistance, Neoplasm D005260:Female D006801:Humans D053758:Nanoparticles D010051:Ovarian Neoplasms D010766:Phosphorylation D011092:Polyethylene Glycols D050796:STAT3 Transcription Factor D000081025:Sphingosine-1-Phosphate Receptors
nanoparticles chemotherapy pH sensitivity antagonist of S1PR1 cisplatin