title: Intrapleural polymeric films containing cisplatin for malignant pleural mesothelioma in a rat tumour model: a preliminary study.
abstract: OBJECTIVE
  This study aims to investigate the effect of intrapleural polymeric films containing cisplatin on the local recurrence of malignant pleural mesothelioma in a rat tumour model.
  
  
  METHODS
  An orthotopic rat recurrence model of malignant pleural mesothelioma was used. Five animals per group were evaluated. Polymeric films (4.5 cm diameter) for the local delivery of anticancer drug were constructed: hyaluronate, chitosan and the combined dual-layer polymers were loaded with cisplatin at a concentration of 100 mgm(-2). Animals without any adjuvant therapy were used as control. Mesothelioma cells were injected subpleurally in the anaesthetised rats. Six days later, a pleural tumour of 5.5mm was resected and a left pneumonectomy and pleural abrasion were performed. Thereafter, the cisplatin-loaded and unloaded films or cisplatin solution were intrapleurally applied, according to randomisation. After 6 days, animals were euthanised and organs harvested for morphological and histological evaluations. The primary endpoint was the volume of tumour recurrence. The secondary endpoints were treatment-related toxicity; cisplatin serum concentration evaluated at different time points; and cisplatin concentration in the pleura measured at autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups.
  
  
  RESULTS
  Tumour volume was significantly reduced in the hyaluronate cisplatin and hyaluronate-chitosan cisplatin groups in comparison to control groups (p=0.001 and p<0.0001, respectively). Animals treated with hyaluronate-chitosan cisplatin had a tumour recurrence significantly lesser than animals treated with cisplatin solution (p=0.003) and hyaluronate cisplatin (p=0.032). No toxicity related to the different treatments was observed. On postoperative days 1 and 2, cisplatin was detected in the serum at a concentration six- and sevenfold significantly higher in the hyaluronate cisplatin and hyaluronate-chitosan cisplatin groups, in comparison to cisplatin solution, and was maintained over time. Cisplatin levels in the pleura were higher in the hyaluronate-chitosan cisplatin group than in all others.
  
  
  CONCLUSIONS
  Hyaluronate-chitosan cisplatin was significantly effective in reducing tumour recurrence compared with cisplatin solution. Hyaluronate and hyaluronate-chitosan loaded with cisplatin assured significantly higher and more prolonged plasmatic drug concentrations than cisplatin solution without increasing toxicity.
authors.affiliation: Thoracic Surgery, University Hospital of Parma, Parma, Italy. lucampollini@inwind.it
authors.forename: Luca
authors.initials: L
authors.lastname: Ampollini
authors.forename: Fabio
authors.initials: F
authors.lastname: Sonvico
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Rocco
authors.initials: R
authors.lastname: Bilancia
authors.forename: Claudio
authors.initials: C
authors.lastname: Mucchino
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cantoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Carbognani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017024:Chemotherapy, Adjuvant / Q000379:methods; D048271:Chitosan; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006820:Hyaluronic Acid; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010997:Pleural Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D011013:Pneumonectomy / Q000379:methods; D011108:Polymers; D051381:Rats; D011916:Rats, Inbred F344; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014677:Pharmaceutical Vehicles; D011108:Polymers; D006820:Hyaluronic Acid; D048271:Chitosan; D002945:Cisplatin