Physicochemical and pharmacokinetic properties of polymeric films loaded with cisplatin for the treatment of malignant pleural mesothelioma

Abstract

Background: Malignant mesothelioma is an invasive neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities. Mesothelioma treatment is unsatisfactory and recurrence is common. Here an innovative locoregional treatment for malignant pleural mesothelioma is presented. Methods: Chitosan-and hyaluronate-based films were loaded with 0.5% and 4% w/w cisplatin and were studied for their physicochemical, mechanical and drug release characteristics. The performance of the drug delivery systems was assessed in vitro on A549 cells and on an orthotopic model of MPM recurrence in rats. Results: Polysaccharide films produced were thin, flexible and resistant. Cisplatin was completely released from hyaluronic acid films within 96 hours, while drug release was found to be much more prolonged with chitosan films. The drug released from hyaluronate films was effective against A549 cell line, while for chitosan films the release was too slow to produce cytotoxicity. Similarly, cisplatin-loaded chitosan films in vivo released minimal quantities of cisplatin and induced inflammation and foreign body reaction. Cisplatinloaded hyaluronate acid films on the contrary were able to prevent tumor recurrence. The cisplatinloaded hyaluronate films provided higher C max and AUC compared to a solution of cisplatin administered intrapleurally, but did not show any sign of treatment related toxicity. Conclusions:Hyaluronate-based films appear as an optimal platform for the development of drug delivery systems suitable for the loco-regional post-surgical treatment of lung malignancies.

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

“…Despite this, the systemic toxicity observed in those animals treated with HYALCIS was significantly lower than all other treatment groups (7). We hypothesized that these encouraging data occurred as a result of the chemic-physical properties of the polymeric films, which allowed for a controlled release of the drug (7,16). …”

“…Cardiac and hemodynamic data and esophageal temperature were recorded by the monitor Guardian Byosis (Schiller, Esaote, Genova, Italy) while respiratory parameters were recorded by the monitor PM8050. f o r m h e r e o n i n ) w e r e u s e d f o r t h i s s t u d y. T h e physicochemical properties of these films together with their characteristics were extensively reported in previous papers (6,16). Briefly, cisplatin was purchased from Sigma-Aldrich (Saint Louis, USA).…”

Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma

“…In humans, 12 to 15 such films would be required to cover the operated chest surface. Film manufacturing is described in the previous publications [ 9 , 10 , 11 , 12 ]. Briefly, the film-forming mixture was prepared as follows: the plasticizing agents, sorbitol (70% w / v ), PEG 1000 stearate and PEG 200, were dissolved in purified water.…”

“…A novel loco-regional treatment to apply to the mesothelium from where the primary tumor has been removed, can improve the existing therapy, directly attacking the site of recurrences. Our group has developed a sodium hyaluronate (NaHA) film loaded with cisplatin (CisPt) for the treatment of mesothelioma [ 9 , 10 , 11 , 12 ]. The film can be stuck to mesothelial surfaces during surgery, determining high and prolonged local cisplatin concentrations at the site where the tumor was removed.…”

Production and Characterization of Glutathione-Chitosan Conjugate Films as Systems for Localized Release of Methotrexate

“…However, different strategies have been created to treat this disease reducing the risk of systemic toxicity. These imply several polymer-based drug delivery systems, which could increase the bioavailability of chemotherapeutic agents in cancer tissues, increasing their solubility and reducing the systemic side effects [5,6]. Thus, diverse delivery devices such as microspheres, patches, polymer films, osmotic pumps, liposomes, polymer-drug conjugates [7] have been developed to reach high drug levels on target tissues [8,9].…”