Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model

Abstract

Background: Malignant pleural mesothelioma (MPM) continues to be a distressing tumor due to its aggressive biologic behavior and scanty prognosis. Several therapeutic approaches have been tested both in clinical and preclinical settings, being intrapleural chemotherapy one of the most promising. Some years ago, our interest focused on polymeric films loaded with cisplatin for the adjuvant intrapleural treatment of surgical patients. After in vitro and in vivo studies in a rat recurrence model of MPM, the aim of this study was to evaluate the pharmacokinetics of the polymeric films in a sheep model in view of further studies in a clinical setting.

Methods: An ovine model was used. Animals were divided into four groups according to pharmacologic treatment: control group (three animals undergoing left pneumonectomy and saline-NaCl solution); intrapleural hyaluronate cisplatin films (HYALCIS) group (six animals undergoing left pneumonectomy and intrapleural application of polymeric films loaded with cisplatin); intrapleural cisplatin solution (six animals undergoing left pneumonectomy and intrapleural application of cisplatin solution); intravenous cisplatin (five animals undergoing left pneumonectomy and intravenous administration of cisplatin solution). The primary objective was the plasmatic and pleural concentration of cisplatin in the treatment groups. The secondary objective was the treatment-related toxicity evaluated by plasmatic analysis performed at prearranged time intervals and histological examinations of tissue samples collected during animal autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups.

Results: Twenty female Sardinian sheep with a mean weight of 45.1 kg were studied. All animals survived the surgical procedures. The whole surgical procedure had a mean duration of 113 minutes. Cisplatin blood levels obtained from polymeric films application were low during the first 24 hours after the application; then, the cisplatin blood level increased gradually and progressively until it reached significantly higher plasmatic concentrations after 120 hours compared to intrapleural cisplatin solution (P=0.004) and intravenous administration (P=0.001), respectively. Considering cisplatin concentration at 168 hours after the application, animals treated with polymeric films had higher plasmatic values than animals treated with intrapleural cisplatin solution and intravenous cisplatin (P=0.001). Despite the high cisplatin plasmatic concentrations, treatment related-toxicity towards kidneys and liver was comparatively lower compared to the intravenous and intrapleural cisplatin administration and closer to the control levels.

Conclusions: Polymeric films loaded with cisplatin allowed to reach significantly higher intrapleural and plasmatic cisplatin concentrations compared to intrapleural and intravenous cisplatin solution, providing at the same time, a significant reduction of treatment related toxicity.

Keywords: Malignant Pleural Mesothelioma (MPM); cisplatin; intrapleural chemotherapy; intrapleural treatment.

Figure 1

Intraoperative view of the pleural cavity and mediastinal structures after left pneumonectomy.

Figure 2

Intraoperative view of the pleural cavity and mediastinum after intrapleural application of the polymeric films. The entire inner surface of the pleural cavity and mediastinal structures appeared homogeneously covered by polymeric films (HYALCIS).

Figure 3

Plasmatic cisplatin drug concentration (ng/mL) during the first 24 hours after adjuvant treatment administration. HYALCIS, intrapleural hyaluronate films loaded with cisplatin; IP cis, intrapleural cisplatin solution; IV cis, intravenous cisplatin solution.

Figure 4

Plasma concentrations of cisplatin from the day of administration to the 9th postoperative day (and beyond for one animal). HYALCIS, intrapleural hyaluronate films loaded with cisplatin; IP cis, intrapleural cisplatin solution; IV cis, intravenous cisplatin solution.

Figure 5

The trend and evolution of plasmatic cisplatin concentration during the entire study period is clearly represented. HYALCIS, intrapleural hyaluronate films loaded with cisplatin; IP cis, intrapleural cisplatin solution; IV cis, intravenous cisplatin solution.

Figure 6

Cisplatin tissue concentration determined at 9th postoperative day (day of autopsy) in the diaphragmatic pleura, diaphragm muscle, parietal pleura, intercostal muscle and pericardium for animals treated with polymeric films loaded with cisplatin (HYALCIS) (green bars), intrapleural cisplatin solution (red bars) and intravenous cisplatin solution (blue bars).

Figure 7

Cisplatin tissue concentration determined in the diaphragmatic pleura, diaphragm muscle, parietal pleura, intercostal muscle and pericardium at different time points: at 24th postoperative day for one single animal treated with polymeric films loaded with cisplatin (HYALCIS) (green bars); at 9th postoperative day for animals treated with intrapleural cisplatin solution (red bars) and intravenous cisplatin solution (blue bars).

Figure 8

Urea (left side) and creatinine (right side) plasmatic concentration measured during the 9 days of experiment according to treatment groups. Control: no adjuvant therapy after pneumonectomy.

Figure 9

Glomerular ectasia and protein ultrafiltration evaluated in animals treated with polymeric films loaded with cisplatin and in all other groups.

Figure 10

Ultrafiltrates in the tubular lumen were significantly more present in sheep receiving intrapleural and intravenous cisplatin solution compared to sheep receiving polymeric films loaded with cisplatin.

Figure 11

Vacuolar degeneration, one of the parameter evaluated for liver toxicity, was higher in sheep receiving intrapleural and intravenous cisplatin solution compared to sheep receiving polymeric films loaded with cisplatin.

Figure S1

Intraoperative view. (A) Dissection and isolation of the left main pulmonary artery; (B) resection of the pulmonary artery by mechanical vascular stapler; (C) appearance of the surgical field after pulmonary artery section.

Figure S2

Intraoperative view. (A) Dissection and isolation of the left superior pulmonary vein; (B) resection of the superior pulmonary vein by mechanical vascular stapler; (C) appearance of the surgical field after superior pulmonary vein section.

Figure S3

Intraoperative view. (A) Dissection and isolation of the left inferior pulmonary vein; (B) resection of the inferior pulmonary vein by mechanical vascular stapler; (C) appearance of the surgical field after inferior pulmonary vein section.

Figure S4

Intraoperative view. (A) Dissection and isolation of the left main bronchus; (B) appearance of the mediastinum after bronchial resection and lung removal.