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

Maofan Zhang; C Tilden Hagan 4th; Yuangzeng Min; Hayley Foley; Xi Tian; Feifei Yang; Yu Mi; Kin Man Au; Yusra Medik; Kyle Roche; Kyle Wagner; Zachary Rodgers; Andrew Z Wang

doi:10.1016/j.biomaterials.2018.03.055

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

Biomaterials. 2018 Jul:169:1-10. doi: 10.1016/j.biomaterials.2018.03.055. Epub 2018 Mar 31.

Authors

Affiliations

¹ Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang, Liaoning, 110122, PR China; Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China.
⁵ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry, Westminster College, New Wilmington, PA 16172, USA.
⁶ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: zawang@med.unc.edu.

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.

Keywords: Combination therapy; Nanoparticle; Ovarian cancer; Platinum resistance; Treatment synergy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Chemoradiotherapy / methods
Cisplatin / administration & dosage*
Cisplatin / pharmacology
Drug Carriers*
Drug Synergism
Female
Humans
Mice
Nanoparticles* / chemistry
Ovarian Neoplasms / drug therapy*
Polyesters / chemistry
Polyethylene Glycols / chemistry
Wortmannin / administration & dosage*
Wortmannin / pharmacology
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Drug Carriers
Polyesters
polyethylene glycol-poly(lactide-co-glycolide)
Polyethylene Glycols
Cisplatin
Wortmannin

Abstract

Publication types

MeSH terms

Substances

Grants and funding