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

Our plain-English summary of Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma, by S. Banella, E. Quarta, P. Colombo, et al (Pharmaceutics, 2021).

The study

• Authors: S. Banella, E. Quarta, P. Colombo, F. Sonvico, A. Pagnoni, F. Bortolotti, G. Colombo
• Journal: Pharmaceutics
• Published: 2021;13(3)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3-4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).

In plain English

This paper was not a study of asbestos exposure, and no patients or animals were tested in it. It described the European Union orphan-medicine designation procedure for a film made of sodium hyaluronate (hyaluronan) loaded with the cancer drug cisplatin. The film is meant to be placed on the chest lining during surgery for malignant pleural mesothelioma. The paper also reported laboratory tests requested by the European Medicines Agency. An earlier sheep study by the same research group had found unexpectedly high blood levels of platinum with the film, so the authors tested whether cisplatin binds to hyaluronan. In the liquid mixture used to make the film, free cisplatin was about 5% of the expected amount, and the authors considered the remaining 95% bound to hyaluronan. In 0.9% salt water at body temperature, 87.9% of the cisplatin from freshly made films was released by 48 hours. Films stored 3 or 7 months dissolved more slowly but released cisplatin in a similar way. The authors concluded that the data confirmed a cisplatin/hyaluronan complex in the film. They noted that a method for measuring the drug in living bodies still needs validation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Description of the EU orphan medicine designation procedure plus a laboratory (in vitro) pharmaceutical study using chromatography, atomic absorption spectroscopy and drug-release tests on films; no new human or animal data (sheep data shown are re-analysed from an earlier study by the group)
• Who was studied: No human or animal subjects; laboratory samples of the cisplatin/hyaluronan film-forming mixture and of films aged 1 day, 3 months and 7 months, with release tests done in triplicate
• Exposure: Not an asbestos exposure study. The test material was a sodium hyaluronate film containing 1% (w/w) cisplatin, tested in water, 0.9% NaCl and 1.8% NaCl at 37 degrees C
• Main results:
  • In size-exclusion chromatography of the film-forming mixture, no clear cisplatin peak was seen, only the hyaluronan peak
  • Platinum was found in the fluid collected at the time hyaluronan came off the column, which the authors read as cisplatin likely bound to the polymer (qualitative only)
  • Free cisplatin in the film-forming mixture was about 5% of the expected amount; the authors considered the other 95% complexed with hyaluronan
  • In water, about 14% of the cisplatin in a fresh film was released in half an hour, after which the measured cisplatin declined, which the authors attributed to hydrolysis
  • In water, a placebo film without cisplatin dissolved completely within 15 minutes, while the cisplatin film was still present at 80 hours
  • In 0.9% NaCl, a 1-day-old film released 18.2 ± 0.2% of its cisplatin in 30 minutes
  • In 0.9% NaCl, cisplatin release from the 1-day-old film reached a plateau at 48 hours with 87.9 ± 4.8% released
  • The fresh drug-loaded film had fully dissolved in saline when about 50% of the drug had been released
  • Films aged 3 and 7 months showed apparently no significant difference in cisplatin release from the fresh film, with at least 88% released in 48 hours in all cases
  • The 3- and 7-month-old films released hyaluronan much more slowly than the fresh film
• The authors' conclusion: The authors concluded that the data confirmed a cisplatin/hyaluronan complex in the film, formed already in the film-forming mixture, with more than 90% of the drug involved in the complex
• Limitations the authors state:
  • Platinum in the collected hyaluronan fraction could only be identified, not accurately measured; only 50% of the expected cisplatin was recovered
  • The film-forming mixture sample was outside the validated concentration range for measuring hyaluronan
  • The ion pair chromatography method lacked specificity for hyaluronan
  • The analytical method for measuring the drug in living bodies (pharmacokinetics) has not yet been validated
  • The change in the film during storage is not yet understood and is still under investigation

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Mesothelioma, Pleural Mesothelioma.

Related studies

• In Vitro Assessment of Cisplatin/Hyaluronan Complex for Loco-Regional Chemotherapy — S. Banella, A. Saraswat, et al. (2023)
• Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model — F. Sonvico, S. Barbieri, et al. (2018)
• Local treatment of malignant pleural mesothelioma with intracavitary cytosine-arabinoside and cisplatin — E. Aitini, E. Pasquini, et al. (1992)
• A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy — S. He, J. Yu, et al. (2022)
• What can independent research for mesothelioma achieve to treat this orphan disease? — A. Guazzelli, P. Meysami, et al. (2019)
• Serum hyaluronan as a disease marker — T.C. Laurent, U.B. Laurent, et al. (1996)

Browse more research in Pharmaceutics, or return to medical research.