Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model

Eur J Pharm Sci. 2018 Oct 15;123:89-97. doi: 10.1016/j.ejps.2018.07.035. Epub 2018 Jul 17.


Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20-50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.

Keywords: Cisplatin; Combination chemotherapy; Implants; Locoregional chemotherapy; Mesothelioma; Pemetrexed disodium; Sodium hyaluronate.

MeSH terms

  • Animals
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Cisplatin* / administration & dosage
  • Cisplatin* / therapeutic use
  • Drug Carriers*
  • Hyaluronic Acid*
  • Lung Neoplasms / drug therapy*
  • Male
  • Mesothelioma / drug therapy*
  • Mesothelioma, Malignant
  • Neoplasm Recurrence, Local / drug therapy
  • Pemetrexed* / administration & dosage
  • Pemetrexed* / therapeutic use
  • Pleural Neoplasms / drug therapy*
  • Rats
  • Rats, Inbred F344


  • Antineoplastic Agents
  • Drug Carriers
  • Pemetrexed
  • Hyaluronic Acid
  • Cisplatin