title: Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model.
abstract: OBJECTIVE
  The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions.
  
  
  METHODS
  Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne(®) 400 μg/kg, fluence rate 200 mW/cm(2) and fluence 60 J/cm(2)) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000 kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody.
  
  
  RESULTS
  PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran.
  
  
  CONCLUSIONS
  Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesothelioma.
authors.affiliation: Division of Thoracic and Vascular Surgery, University Hospital of Lausanne, CHUV, Lausanne, Switzerland.
authors.forename: Yabo
authors.initials: Y
authors.lastname: Wang
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Perentes
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schäfer
authors.forename: Michel
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Elodie
authors.initials: E
authors.lastname: Debefve
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.forename: Thorsten
authors.initials: T
authors.lastname: Krueger
mesh_terms: D000818:Animals; D003911:Dextrans / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011166:Porphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D000077362:Verteporfin
chemical_list: D003911:Dextrans; D017319:Photosensitizing Agents; D011166:Porphyrins; C015219:fluorescein isothiocyanate dextran; D000077362:Verteporfin; D016650:Fluorescein-5-isothiocyanate