Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models. (July 2018)

• Record Type: Journal Article
• Authors: Zhang, Maofan; Hagan, C. Tilden; Min, Yuangzeng; Foley, Hayley; Tian, Xi; Yang, Feifei; Mi, Yu; Au, Kin Man; Medik, Yusra; Roche, Kyle; Wagner, Kyle; Rodgers, Zachary; Wang, Andrew Z.
• Is Part Of: Biomaterials. Volume 169(2018)
• Page Start: 1
• Page End: 10
• Publication Date: 2018-07
• Subjects: Nanoparticle -- Combination therapy -- Platinum resistance -- Treatment synergy -- Ovarian cancer; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2018.03.055
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.