Surface-Modified Inhaled Microparticle-Encapsulated Celastrol for Enhanced Efficacy in Malignant Pleural Mesothelioma

Our plain-English summary of Surface-Modified Inhaled Microparticle-Encapsulated Celastrol for Enhanced Efficacy in Malignant Pleural Mesothelioma, by X. Wang, G. Chauhan, A.R.L. Tacderas, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: X. Wang, G. Chauhan, A.R.L. Tacderas, A. Muth, V. Gupta
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(6)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer affecting the pleural lining of the lungs. Celastrol (Cela), a pentacyclic triterpenoid, has demonstrated promising therapeutic potential as an antioxidant, anti-inflammatory, neuroprotective agent, and anti-cancer agent. In this study, we developed inhaled surface-modified Cela-loaded poly(lactic-co-glycolic) acid (PLGA) microparticles (Cela MPs) for the treatment of MPM using a double emulsion solvent evaporation method. The optimized Cela MPs exhibited high entrapment efficiency (72.8 ± 6.1%) and possessed a wrinkled surface with a mean geometric diameter of ~2 µm and an aerodynamic diameter of 4.5 ± 0.1 µm, suggesting them to be suitable for pulmonary delivery. A subsequent release study showed an initial burst release up to 59.9 ± 2.9%, followed by sustained release. The therapeutic efficacy of Cela MPs was evaluated against four mesothelioma cell lines, where Cela MP exhibited significant reduction in IC50 values, and blank MPs produced no toxicity to normal cells. Additionally, a 3D-spheroid study was performed where a single dose of Cela MP at 1.0 µM significantly inhibited spheroid growth. Cela MP was also able to retain the antioxidant activity of Cela only while mechanistic studies revealed triggered autophagy and an induction of apoptosis. Therefore, these studies highlight the anti-mesothelioma activity of Cela and demonstrate that Cela MPs are a promising inhalable medicine for MPM treatment.

In plain English

This laboratory study did not examine asbestos exposure. It tested an experimental inhaled drug form for malignant pleural mesothelioma in cells grown in the lab. The authors packaged celastrol, a plant-derived compound, inside small biodegradable PLGA polymer particles. The particles held 72.8 ± 6.1% of the drug added, had a wrinkled surface about 2 µm across, and had an aerodynamic diameter of 4.5 ± 0.1 µm, which the authors considered suitable for deep lung delivery. In four mesothelioma cell lines, the particle form cut cell viability by half at lower concentrations than plain celastrol. In H2452 cells, for example, this value (the IC50) fell from 18.7 ± 0.1 µM to 3.8 ± 0.1 µM. In a 48-hour viability test, empty particles caused no appreciable toxicity to one mesothelioma cell line, MSTO-211H, or to normal lung fibroblasts at the concentrations tested. In 3D tumor spheroids, one 1.0 µM dose of the particles suppressed growth about 13-fold compared with untreated spheroids. No animals or patients were tested. The authors concluded the particles are a promising inhaled therapy for this cancer. They noted that their lab tests were likely inadequate to fully predict preclinical behavior.

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: Laboratory (in vitro) study: development of a celastrol-loaded polymer microparticle formulation, followed by tests in mesothelioma cell cultures and 3D tumor spheroids. No animal or human testing.
• Who was studied: Cell lines, not people. Three immortalized malignant pleural mesothelioma cell lines (MSTO-211H, H28, H2452) came from ATCC. One primary patient-derived mesothelioma cell line (ROB) came from the National Cancer Institute. Normal human lung fibroblasts (NHLF) were used to check the toxicity of empty particles. The 3D spheroids were made from MSTO-211H cells.
• Exposure: No asbestos exposure was studied. The treatment studied was celastrol, alone or encapsulated in PLGA microparticles made with sodium chloride. Spheroids received 0.5 and 1.0 µM celastrol concentrations, as single or multiple doses.
• Main results:
  • The optimized microparticles had a mass median aerodynamic diameter of 4.5 ± 0.1 µm. This is within the 2–5 µm range the authors cite for delivery to the respirable region of the lungs.
  • In simulated lung fluid, 59.9 ± 2.9% of celastrol was released from the microparticles after 30 minutes. Sustained release followed, reaching 81.0 ± 1.0% by 72 hours.
  • In MSTO-211H cells, the IC50 was 3.6 ± 0.4 µM for plain celastrol and 2.7 ± 0.3 µM for the microparticles. This was about 1.3-fold lower (p less than 0.05).
  • IC50 values for plain celastrol versus microparticles were 12.9 ± 3.3 vs 3.8 ± 0.6 µM in H28 cells, 18.7 ± 0.1 vs 3.8 ± 0.1 µM in H2452 cells, and 3.5 ± 0.2 vs 2.3 ± 0.3 µM in ROB cells. These were reductions of about 3.4-, 5- and 1.5-fold.
  • Empty (drug-free) microparticles were tested in an MTT viability assay after 48 hours, at concentrations corresponding to 0.10–6.25 µM celastrol. They caused no appreciable toxicity, and viability stayed at about 100% in MSTO-211H mesothelioma cells and in normal human lung fibroblasts. No other mesothelioma lines were tested with empty particles.
  • In MSTO-211H cells after 6 hours, 1.0 µM celastrol microparticles raised caspase-3 (an apoptosis marker) to 503.1 ± 93.1% of control. This was about a 5-fold increase over control and about 3.5-fold over 1.0 µM plain celastrol (143 ± 19.7%).
  • In MSTO-211H cells, celastrol microparticles increased the autophagy marker (LC3) signal about 1.3-fold relative to control and about 1.5-fold relative to plain celastrol. The text gives the dose as 5 µM in one sentence and as 1.0 µM in the next.
  • In single-dose MSTO-211H spheroids after 15 days, 1.0 µM celastrol microparticles suppressed growth about 13-fold versus control (p less than 0.0001). They suppressed growth about 10-fold versus 1.0 µM plain celastrol (p less than 0.0001).
  • In the multiple-dose spheroid study, all four treatments suppressed growth compared with control: 0.5 µM celastrol about 1.5-fold, 0.5 µM microparticles about 7.6-fold, 1.0 µM celastrol about 3.5-fold, and 1.0 µM microparticles about 11.7-fold.
  • In a free-radical scavenging (antioxidant) test after 24 hours, 5 µM plain celastrol showed 15.7 ± 1.9% scavenging activity. The 5 µM microparticles showed 30.2 ± 4.1%.
• The authors' conclusion: The authors concluded that inhaled celastrol microparticles are a promising standalone anti-cancer therapy for malignant pleural mesothelioma. They said they plan to study the particles in vivo and to evaluate long-term safety and stability.
• Limitations the authors state:
  • The authors stated that the in vitro assays were likely inadequate to fully predict the preclinical behavior of the microparticles. They noted that monolayer cell studies lack the properties of a solid tumor.
  • The formulation produced wrinkled rather than porous particles, contrary to the intended porous design.
  • The authors noted that the particle size range achieved had previously been shown to be ideal for uptake by immune cells (phagocytosis).

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

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

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