title: Localization of liposomal mTHPC formulations within normal epithelium, dysplastic tissue, and carcinoma of oral epithelium in the 4NQO-carcinogenesis rat model.
abstract: OBJECTIVE
  Foslip and Fospeg are liposomal formulations of the photosensitizer mTHPC (Foscan), which is used for photodynamic therapy (PDT) of malignancies. Literature suggests that liposomal mTHPC formulations have better properties and increased tumor uptake compared to Foscan. To investigate this, we used the 4NQO-induced carcinogen model to compare the localization of the different mTHPC formulations within normal, precancerous, and cancerous tissue. In contrast to xenograft models, the 4NQO model closely mimics the carcinogenesis of human oral dysplasia.
  
  
  METHODS
  Fifty-four rats drank water with the carcinogen 4NQO. When oral examination revealed tumor, the rats received 0.15 mg/kg mTHPC (Foscan, Foslip, or Fospeg). At 2, 4, 8, 24, 48, or 96 hours after injection the rats were sacrificed. Oral tissue was sectioned for HE slides and for fluorescence confocal microscopy. The HE slides were scored on the severity of dysplasia by the epithelial atypia index (EAI). The calibrated fluorescence intensity per formulation or time point was correlated to EAI.
  
  
  RESULTS
  Fospeg showed higher mTHPC fluorescence in normal and tumor tissue compared to both Foscan and Foslip. Significant differences in fluorescence between tumor and normal tissue were found for all formulations. However, at 4, 8, and 24 hours only Fospeg showed a significant difference. The Pearson's correlation between EAI and mTHPC fluorescence proved weak for all formulations.
  
  
  CONCLUSIONS
  In our induced carcinogenesis model, Fospeg exhibited a tendency for higher fluorescence in normal and tumor tissue compared to Foslip and Foscan. In contrast to Foscan and Foslip, Fospeg showed significantly higher fluorescence in tumor versus normal tissue at earlier time points, suggesting a possible clinical benefit compared to Foscan. Low correlation between grade of dysplasia and mTHPC fluorescence was found.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Sebastiaan A H J
authors.initials: SA
authors.lastname: de Visscher
authors.forename: Max J H
authors.initials: MJ
authors.lastname: Witjes
authors.forename: Bert
authors.initials: B
authors.lastname: van der Vegt
authors.forename: Henriëtte S
authors.initials: HS
authors.lastname: de Bruijn
authors.forename: Angélique
authors.initials: A
authors.lastname: van der Ploeg-van den Heuvel
authors.forename: Arjen
authors.initials: A
authors.lastname: Amelink
authors.forename: Henricus J C M
authors.initials: HJ
authors.lastname: Sterenborg
authors.forename: Jan L N
authors.initials: JL
authors.lastname: Roodenburg
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Robinson
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D008652:Mesoporphyrins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009061:Mouth Mucosa / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D015588:Observer Variation; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002273:Carcinogens; D008081:Liposomes; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D015112:4-Nitroquinoline-1-oxide; C072269:temoporfin
keywords: 4-nitroquinoline-1-oxide; carcinogenesis; confocal microscopy; fluorescence microscopy; liposomes; meta-tetra(hydroxyphenyl)chlorine