title: Assessment of the specificity of a new folate-targeted photosensitizer for peritoneal metastasis of epithelial ovarian cancer to enable intraperitoneal photodynamic therapy. A preclinical study.
abstract: BACKGROUND
  Ovarian cancer's prognosis remains dire after primary therapy. Recurrence rate is disappointingly high as 60% of women with epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis during surgery is necessary as they are the main predictive factors of recurrences. Folate Receptor α (FRα) shows promising prospects in targeting ovarian cancerous cells and intraperitoneal photodynamic therapy (PDT) could be a solution in addition to macroscopic cytoreductive surgery to treat peritoneal micrometastasis. The aim of this preclinical study is to assess the specificity of a folate-targeted photosensitizer for ovarian peritoneal micrometastasis.
  
  
  METHODS
  We used the NuTu-19 epithelial ovarian cancer cell line to induce peritoneal carcinomatosis in female Fischer 344 rats. Three groups of 6 rats were studied (Control (no photosensitizer)/Non-conjugated photosensitizer (Porph)/Folate-conjugated photosensitizer (Porph-s-FA)). Four hours after the administration of the photosensitizer, animals were sacrificed and intraperitoneal organs tissues were sampled. FRα tissue expression was evaluated by immunohistochemistry. Tissue incorporation of photosensitizers was assessed by confocal microscopy and tissue quantification.
  
  
  RESULTS
  FRα is overexpressed in tumor, ovary, and liver whereas, peritoneum, colon, small intestine, and kidney do not express it. Cytoplasmic red endocytosis vesicles observed by confocal microscopy are well correlated to FRα tissue expression. Photosensitizer tissue quantification shows a mean tumor-to-normal tissue ratio of 9.6.
  
  
  CONCLUSIONS
  We demonstrated that this new generation folate-targeted photosensitizer is specific of epithelial ovarian peritoneal metastasis and may allow the development of efficient and safe intraperitoneal PDT procedure.
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Gynecology, University of Lille, 59000 Lille, France. Electronic address: henriazais@gmail.com.
authors.forename: Henri
authors.initials: H
authors.lastname: Azaïs
authors.affiliation: Centre Français des Porphyries, Assistance Publique - Hôpitaux de Paris, Hôpital Louis Mourier, Colombes, France and INSERM U1149, Paris Diderot University, 75018 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Plate-Forme D'imagerie Cellulaire BICEL - IFR 114, Pôle Recherche, University of Lille, 59000 Lille, France.
authors.forename: Meryem
authors.initials: M
authors.lastname: Tardivel
authors.affiliation: Centre de Biologie-Pathologie, University of Lille, 59000 Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kerdraon
authors.affiliation: Laboratoire Réactions et Génie des Procédés, UMR 7274CNRS - University of Lorraine, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Stallivieri
authors.affiliation: Laboratoire Réactions et Génie des Procédés, UMR 7274CNRS - University of Lorraine, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Frochot
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France.
authors.forename: Nacim
authors.initials: N
authors.lastname: Betrouni
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France; Department of Gynecology, University of Lille, 59000 Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Collinet
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, F-59000 Lille, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Mordon
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism*; D005492:Folic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D058990:Molecular Targeted Therapy / Q000379:methods; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D011166:Porphyrins / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
chemical_list: D058975:Folate Receptor 1; D017319:Photosensitizing Agents; D011166:Porphyrins; D005492:Folic Acid
keywords: Folate receptor; Ovarian peritoneal carcinomatosis; Photodynamic therapy; Photosensitizer; Targeted-therapy