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Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models

Authors :
Xi Tian
Kyle C. Roche
Kin Man Au
Andrew Z. Wang
Feifei Yang
Yu Mi
Yuangzeng Min
Kyle Wagner
C. Tilden Hagan
Hayley Foley
Zachary L. Rodgers
Yusra Medik
Maofan Zhang
Source :
Biomaterials. 169:1-10
Publication Year :
2018
Publisher :
Elsevier BV, 2018.

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.

Details

ISSN :
01429612
Volume :
169
Database :
OpenAIRE
Journal :
Biomaterials
Accession number :
edsair.doi.dedup.....469b51390dfd81c18c7ea1cb8c5a9943
Full Text :
https://doi.org/10.1016/j.biomaterials.2018.03.055