title: Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities.
abstract: BACKGROUND
  Low-dose, Visudyne®-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin®) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities.
  
  
  METHODS
  Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne®, 10 J/cm(2) ) followed by IV administration of Lipoplatin® (5 mg/kg) and the other half received Lipoplatin® without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne®; 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin® administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin® immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin® and VATS pleural biopsies but no photo-induction (controls). Lipoplatin® concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry.
  
  
  RESULTS
  Photo-induction selectively increased Lipoplatin® uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin® concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin® was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin® concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 ± 0.7 vs. 1.37 ± 0.7 ng/mg, P  < 0.001).
  
  
  CONCLUSIONS
  Visudyne®-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin® in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Departement of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gronchi
authors.affiliation: Central Environmental Laboratory, Swiss Federal Institute of Technology(EPFL), Lausanne, VD, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Bensimon
authors.affiliation: Departement of Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercier
authors.affiliation: Departement of Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Laurent Arthur
authors.initials: LA
authors.lastname: Decosterd
authors.affiliation: Central Environmental Laboratory, Swiss Federal Institute of Technology(EPFL), Lausanne, VD, Switzerland.
authors.forename: Georges
authors.initials: G
authors.lastname: Wagnières
authors.affiliation: Departement of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Debefve
authors.affiliation: Departement of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Hans-Beat
authors.initials: HB
authors.lastname: Ris
authors.affiliation: Department of Pathology, University of Lausanne, Lausanne, VD, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.affiliation: Departement of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Peters
authors.affiliation: Departement of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland.
authors.forename: Jean Yannis
authors.initials: JY
authors.lastname: Perentes
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy; D009368:Neoplasm Transplantation; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011166:Porphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D012509:Sarcoma / Q000188:drug therapy; D013552:Swine; D016896:Treatment Outcome; D000077362:Verteporfin
chemical_list: D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; C503131:lipoplatin; D000077362:Verteporfin; D002945:Cisplatin
keywords: adenocarcinoma; chemotherapy; lipoplatin; lung; mesothelioma; minipig; photodynamic therapy; rodent; sarcoma; visudyne