In Vitro Assessment of Cisplatin/Hyaluronan Complex for Loco-Regional Chemotherapy

Our plain-English summary of In Vitro Assessment of Cisplatin/Hyaluronan Complex for Loco-Regional Chemotherapy, by S. Banella, A. Saraswat, A. Patel, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: S. Banella, A. Saraswat, A. Patel, A.T.M. Serajuddin, P. Colombo, K. Patel, G. Colombo
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(21)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Loco-regional chemotherapy is a strategy used to achieve more precise anticancer drug effect directly on tumor mass, while decreasing whole body exposure, which can lead to undesirable side effects. Thus, the loco-regional chemotherapy is conceptually similar to the targeted drug delivery systems for delivering chemotherapeutics to cancer cells in a certain location of the body. Recently, it has been demonstrated that a novel polymeric film containing the complex between cisplatin (cisPt) and hyaluronan (sodium salt of hyaluronic acid; NaHA) enhanced in vivo efficacy and safety of cisplatin (cisPt) by loco-regional delivery in pleural mesothelioma. Biologically, hyaluronic acid (HA) binds with the CD44 receptor, which is a transmembrane glycoprotein overexpressed by other cancer cells. Thus, administering both cisPt and hyaluronan together as a complex loco-regionally to the tumor site could target cancer cells locally and enhance treatment safety. A slight excess of hyaluronan was required to have more than 85% cisPt complexation. In cell monolayers (2D model) the cisPt/NaHA complex in solution demonstrated dose- and time-dependent cytotoxic effect by decreasing the viability of pancreatic, melanoma, and lung cell lines (they all express CD44). At the same concentration in solution, the complex was as effective as cisPt alone. However, when applied as film to melanoma spheroids (3D model), the complex was superior because it prevented the tumor spheroid growth and, more importantly, the formation of new cell colonies. Hence, cisPt/NaHA complex could work in preventing metastases loco-regionally and potentially avoiding systemic relapses.

In plain English

This laboratory study tested a complex of the cancer drug cisplatin with hyaluronan (sodium hyaluronate), the base of a drug-releasing film developed earlier for pleural mesothelioma. It studied no asbestos exposure, no mesothelioma cells, no animals and no patients. The authors used human pancreatic, lung and melanoma cancer cell lines grown as flat layers, and melanoma cells grown as small 3D clusters called spheroids. In flat layers, the complex killed cells about as well as cisplatin alone, with no statistically significant difference overall. Adding valproic acid gave no extra effect. In smaller spheroids treated with drug solutions, the complex and cisplatin alone slowed growth similarly compared with untreated spheroids, but did not stop it. In larger spheroids placed on the film, or given a cisplatin solution washed out over 6 hours, area stayed substantially unchanged over 6 days while untreated spheroids doubled in area; new cell colonies formed only in the untreated and solution groups. The authors concluded that complexing did not compromise cisplatin's activity, and they recommended testing in an animal model of melanoma.

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: In vitro laboratory experiment on cancer cell lines grown as 2D monolayers and as 3D spheroids
• Who was studied: Human cancer cell lines: pancreatic (BxPC3, MIA PaCa-2), lung (A549) and melanoma (A375, both vemurafenib-responsive and vemurafenib-resistant), plus a kidney cell line (HEK293). No mesothelioma cells, animals or humans were studied.
• Exposure: No asbestos exposure. Treatments were cisplatin alone; cisplatin complexed with sodium hyaluronate of high (1330 kDa) or low (10 kDa) molecular weight; cisplatin plus valproic acid; and a cisplatin-loaded hyaluronan film previously developed for loco-regional treatment of pleural mesothelioma.
• Main results:
  • About 3.6 parts of high molecular weight hyaluronan (monomer) per 1 part cisplatin was the minimum needed to complex at least 85% of the cisplatin.
  • In 2D cell layers, cell death was comparable for cisplatin alone and the cisplatin/hyaluronan complex, with no statistically significant difference regardless of concentration. There were two exceptions: the complex was less cytotoxic in BxPC3 cells at 12.5 µM, and more cytotoxic in A549 cells at 6.25 µM (p less than 0.05).
  • IC50 values (µM, mean plus or minus SEM, n = 6), cisplatin alone versus complex: BxPC3 9.63 vs 10.58; A549 9.44 vs 9.14; MIA PaCa-2 5.04 vs 5.03; vemurafenib-responsive A375 2.17 vs 2.32. Adding valproic acid made no difference.
  • In melanoma spheroids treated with drug solutions, no treatment prevented spheroid growth. The cisplatin-containing treatments, including the complex, slowed growth compared with untreated controls.
  • In large vemurafenib-resistant A375 spheroids, both the film (cisplatin 100 µM) and a 25 µM cisplatin solution kept spheroid area substantially unchanged over 6 days. Untreated spheroids doubled in area. The solution was progressively diluted to zero over the first 6 hours.
  • New cell colonies grew from spheroids in the untreated and cisplatin solution groups, but no colonies formed in the film group.
  • In a kidney cell line (HEK293), cisplatin alone and both complexes reduced cell viability in a similar, concentration-dependent way.
• The authors' conclusion: The authors concluded that complexing with hyaluronic acid did not compromise cisplatin's anticancer activity in 2D cells, and that cisplatin and the complex had comparable activity on spheroid growth. They recommended further study of the complex in an animal model of melanoma.
• Limitations the authors state:
  • Free cisplatin could not be measured after dilution in culture medium, so the authors could not verify whether the complex broke apart.
  • Uptake of cisplatin by the cells was not measured.
  • Targeting via the CD44 receptor cannot be demonstrated in vitro, because the drug is placed in direct contact with the cells.
  • Spheroids are not a whole organism, so effects such as the lower kidney toxicity seen in earlier animal work are unlikely to be confirmed in a cell model.
  • Cell lines differed in sensitivity, which made it difficult to draw a conclusion about the effect of hyaluronan molecular weight.
  • The early reduction in spheroid area with the film was of uncertain meaning, because the area increased again over the following days.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Chemotherapy, Hyaluronic Acid, Pleural Mesothelioma, Glycoprotein.

Related studies

• Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma — S. Banella, E. Quarta, et al. (2021)
• 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)
• Unusual cases: melanomatosis and nephroblastomatosis treated with hyperthermic intraperitoneal chemotherapy — A. Hayes-Jordan, H. Green, et al. (2012)
• Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection — D.J. Sugarbaker, R.R. Gill, et al. (2013)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure — M. Ried, K. Lehle, et al. (2015)

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