Nanoparticle Co-delivery of Carboplatin and PF543 Restores Platinum Sensitivity in Ovarian Cancer Models Through Inhibiting Platinum-induced Pro-survival Pathway Activation

Overview

Journal Nanoscale Adv

Publisher Royal Society of Chemistry

Specialty Biotechnology

Date 2024 Aug 8

PMID 39114142

Authors

Chen Wang

Qing Li

Keqi Song

Wenjing Wang

Ning Zhang

Lan Dai

Wen Di

Affiliations

Soon will be listed here.

Abstract

Resistance to platinum-based chemotherapy is the major cause of poor prognosis and cancer-associated mortality in ovarian cancer patients, so novel therapeutic strategies to restore platinum sensitivity are needed to improve patient outcomes. Sphingosine Kinase (SphK) 1 is involved in regulating multiple pro-survival pathways, key mediators in the sensitivity of tumor cells toward platinum. By encapsulating CBP and the SphK1 inhibitor PF543 in PLGA (poly lactic--glycolic acid) nanoparticles, a dual-drug delivery system (C/PNPs) was formed to simultaneously deliver CBP and PF543. The physicochemical characteristics, cell uptake rate and biodistribution behavior of C/PNPs were evaluated. Then the anti-tumor ability of C/PNPs and was further investigated. The C/PNPs could deliver CBP and PF543 simultaneously to a platinum-insensitive cell line (SKOV3) both and . Furthermore, benefiting from the enhanced permeability and retention (EPR) effect of PLGA NPs, C/PNPs exhibited an improved tumor region accumulation. As a result, a synergistic anti-tumor effect was found in the SKOV3 tumor-bearing mice, with tumor volume inhibiting rates of 84.64% and no side effects in major organs. The mechanistic studies confirmed that the inhibition of SphK1 by PF543 sensitized SKOV3 cells to CBP chemotherapy, partly by inhibiting the CBP-induced activation of pro-survival pathways, including ERK, AKT and STAT3 signaling. Our study reveals that C/PNPs can serve as an efficient dual-drug delivery system to restore platinum sensitivity in ovarian cancer models partly through inhibiting platinum-induced pro-survival pathway activation.

Citing Articles

Platinum nanoparticles in cancer therapy: chemotherapeutic enhancement and ROS generation.

Faderin E, Iorkula T, Aworinde O, Awoyemi R, Awoyemi C, Acheampong E Med Oncol. 2025; 42(2):42.

PMID: 39789336 DOI: 10.1007/s12032-024-02598-w.

Nanotechnology and nanobots unleashed: pioneering a new era in gynecological cancer management - a comprehensive review.

Kumar N, Mangla M Cancer Chemother Pharmacol. 2025; 95(1):18.

PMID: 39754614 DOI: 10.1007/s00280-024-04747-4.

References

Perry J, Reuter K, Luft J, Pecot C, Zamboni W, DeSimone J . Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location. Nano Lett. 2017; 17(5):2879-2886. PMC: 5708115. DOI: 10.1021/acs.nanolett.7b00021. View

Cheng S, Xu C, Jin Y, Li Y, Zhong C, Ma J . Artificial Mini Dendritic Cells Boost T Cell-Based Immunotherapy for Ovarian Cancer. Adv Sci (Weinh). 2020; 7(7):1903301. PMC: 7141030. DOI: 10.1002/advs.201903301. View

Liang J, Nagahashi M, Kim E, Harikumar K, Yamada A, Huang W . Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013; 23(1):107-20. PMC: 3578577. DOI: 10.1016/j.ccr.2012.11.013. View

Gao Y, Gao F, Chen K, Tian M, Zhao D . Sphingosine kinase 1 as an anticancer therapeutic target. Drug Des Devel Ther. 2015; 9:3239-45. PMC: 4484649. DOI: 10.2147/DDDT.S83288. View

Iqbal M, Zafar N, Fessi H, Elaissari A . Double emulsion solvent evaporation techniques used for drug encapsulation. Int J Pharm. 2015; 496(2):173-90. DOI: 10.1016/j.ijpharm.2015.10.057. View

Mehlich D, Lomiak M, Sobiborowicz A, Mazan A, Dymerska D, Szewczyk L . MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance. Cell Death Dis. 2021; 12(12):1111. PMC: 8627512. DOI: 10.1038/s41419-021-04405-0. View

Zhang H, Wang Q, Zhao Q, Di W . MiR-124 inhibits the migration and invasion of ovarian cancer cells by targeting SphK1. J Ovarian Res. 2013; 6(1):84. PMC: 3879084. DOI: 10.1186/1757-2215-6-84. View

Xu C, Liu W, Hu Y, Li W, Di W . Bioinspired tumor-homing nanoplatform for co-delivery of paclitaxel and siRNA-E7 to HPV-related cervical malignancies for synergistic therapy. Theranostics. 2020; 10(7):3325-3339. PMC: 7053183. DOI: 10.7150/thno.41228. View

Wang C, Ye T, Wang W, Song K, Zhu J, Dai L . Sphingosine kinase 1 contributes to the metastatic potential of epithelial ovarian cancer to the adipocyte-rich niche. Exp Hematol Oncol. 2022; 11(1):102. PMC: 9667684. DOI: 10.1186/s40164-022-00358-y. View

10.

Zielinska A, Carreiro F, Oliveira A, Neves A, Pires B, Venkatesh D . Polymeric Nanoparticles: Production, Characterization, Toxicology and Ecotoxicology. Molecules. 2020; 25(16). PMC: 7464532. DOI: 10.3390/molecules25163731. View

11.

Singh P, Priya E, Balakrishnan S, Arunkumar R, Sharmila G, Rajalakshmi M . Nimbolide inhibits androgen independent prostate cancer cells survival and proliferation by modulating multiple pro-survival signaling pathways. Biomed Pharmacother. 2016; 84:1623-1634. DOI: 10.1016/j.biopha.2016.10.076. View

12.

Li R, He Y, Zhang S, Qin J, Wang J . Cell membrane-based nanoparticles: a new biomimetic platform for tumor diagnosis and treatment. Acta Pharm Sin B. 2018; 8(1):14-22. PMC: 5985624. DOI: 10.1016/j.apsb.2017.11.009. View

13.

Young J, Hua X, Somsel H, Reichart F, Kessler H, Spatz J . Integrin Subtypes and Nanoscale Ligand Presentation Influence Drug Sensitivity in Cancer Cells. Nano Lett. 2020; 20(2):1183-1191. PMC: 7020138. DOI: 10.1021/acs.nanolett.9b04607. View

14.

Cuvillier O . Downregulating sphingosine kinase-1 for cancer therapy. Expert Opin Ther Targets. 2008; 12(8):1009-20. DOI: 10.1517/14728222.12.8.1009. View

15.

Maksimenko O, Malinovskaya J, Shipulo E, Osipova N, Razzhivina V, Arantseva D . Doxorubicin-loaded PLGA nanoparticles for the chemotherapy of glioblastoma: Towards the pharmaceutical development. Int J Pharm. 2019; 572:118733. DOI: 10.1016/j.ijpharm.2019.118733. View

16.

Tazzari P, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T . Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 2007; 21(3):427-38. DOI: 10.1038/sj.leu.2404523. View

17.

Parashar D, Geethadevi A, Mittal S, McAlarnen L, George J, Kadamberi I . Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance. Cancers (Basel). 2022; 14(4). PMC: 8870411. DOI: 10.3390/cancers14040958. View

18.

Jayson G, Kohn E, Kitchener H, Ledermann J . Ovarian cancer. Lancet. 2014; 384(9951):1376-88. DOI: 10.1016/S0140-6736(13)62146-7. View

19.

Nagahashi M, Hait N, Maceyka M, Avni D, Takabe K, Milstien S . Sphingosine-1-phosphate in chronic intestinal inflammation and cancer. Adv Biol Regul. 2013; 54:112-20. PMC: 3946530. DOI: 10.1016/j.jbior.2013.10.001. View

20.

Ma Y, Xing X, Kong R, Cheng C, Li S, Yang X . SphK1 promotes development of non‑small cell lung cancer through activation of STAT3. Int J Mol Med. 2020; 47(1):374-386. DOI: 10.3892/ijmm.2020.4796. View