Journal
BIOMATERIALS
Volume 169, Issue -, Pages 1-10Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.03.055
Keywords
Nanoparticle; Combination therapy; Platinum resistance; Treatment synergy; Ovarian cancer
Funding
- National Institutes of Health/National Cancer Institute [R01CA17848-01, R21 CA182322, U54CA198999]
- Carolina Cancer Nanotechnology T32 Training Program (CCNTP) [NIH- 1T32CA196589]
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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. (C) 2018 Elsevier Ltd. All rights reserved.
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