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

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 ovar...

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Bibliographic Details
Published in:Biomaterials 2018-07, Vol.169, p.1-10
Main 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.
Format: Article
Language:English
Subjects:
adverse effects
animal models
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Chemoradiotherapy - methods
cisplatin
Cisplatin - administration & dosage
Cisplatin - pharmacology
Combination therapy
DNA repair
Drug Carriers
Drug Synergism
drug therapy
Female
Humans
Mice
Nanoparticle
nanoparticles
Nanoparticles - chemistry
Ovarian cancer
ovarian neoplasms
Ovarian Neoplasms - drug therapy
patients
phenotype
platinum
Platinum resistance
Polyesters - chemistry
Polyethylene Glycols - chemistry
relapse
Treatment synergy
Wortmannin - administration & dosage
Wortmannin - pharmacology
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2018.03.055