title: Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer.
abstract: BACKGROUND
  Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin.
  
  
  METHODS
  Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects.
  
  
  RESULTS
  We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model.
  
  
  CONCLUSIONS
  Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Miriana
authors.initials: M
authors.lastname: Hijaz
authors.affiliation: Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, University of Central Florida, Orlando, FL, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.|Wayne State University, Detroit, MI, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Mert
authors.affiliation: Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, University of Central Florida, Orlando, FL, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Wahab
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Tebbe
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Sajad
authors.initials: S
authors.lastname: Dar
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Jasdeep
authors.initials: J
authors.lastname: Chhina
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.|Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.|Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Munkarah
authors.affiliation: Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, University of Central Florida, Orlando, FL, USA.|College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Seal
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA. rrattan1@hfhs.org.|Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA. rrattan1@hfhs.org.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002563:Cerium / Q000008:administration & dosage* / Q000737:chemistry; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D058975:Folate Receptor 1 / Q000096:biosynthesis; D005492:Folic Acid / Q000008:administration & dosage / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D002563:Cerium; C030583:ceric oxide; D005492:Folic Acid; D002945:Cisplatin
keywords: A2780; Folic acid conjugated nanoceria; Nano cerium oxide; Ovarian cancer; Targeted therapy