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

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.

Polymer Microspheres and Their Application in Cancer Diagnosis and Treatment

“…Lignans, found in herbal botanicals, have shown therapeutic benefits against malignant tumors, with microspheres serving as carriers to enhance solubility and bioavailability [ 72 ]. Similarly, the therapeutic potential of celastrol from radix rehmanniae is constrained by its low water solubility, bioavailability, and narrow therapeutic range; however, utilizing microspheres as carriers can amplify its therapeutic effects and mitigate toxicity [ 73 ].…”

“…Carboxymethyl cellulose Breast cancer [66] Carboxymethyl starch Colorectal cancer [69] Gelatin Osteosarcoma [20] Gelatin Hepatocellular carcinoma [19] Gelatin/methacrylated alginate hydrogel composite Gastric cancer [71] Hyaluronic acid Non-small-cell lung cancer [5] Methacrylate fish gelatin Gastric cancer [42] Methacrylate gelatin Melanoma/Breast cancer [75] PLA Melanoma [74] PLGA Lung cancer [68] PLGA Osteosarcoma [27] PLGA Malignant pleural mesothelioma [73] PLGA Non-small-cell lung cancer [28] Polybutylene adipate co-terephthalate/polyvinylpyrrolidone composite Non-small-cell lung cancer [76] Porous hydroxyapatite/gelatin composite Osteosarcoma [67] Immunotherapy Chitosan/sodium alginate composite Colorectal cancer [77] Gelatin Ovary carcinoma [78] Hyaluronic acid Pancreatic ductal adencarcinoma [79] Methacrylate gelatin/methacrylate hyaluronic acid composite Breast cancer [80] PLGA Breast cancer/melanoma [81] PLGA Melanoma [82] Poly(ethylene glycol)diacrylate Non-small-cell lung cancer [83] Poly(N-isopropylacrylamide) Melanoma [84] Polyanhydride copolymer Head and neck squamous cell carcinoma [85] Silk fibroin Melanoma [21] Physiotherapy Alginate Hepatocellular carcinoma [18] Calcium alginate Hepatocellular carcinoma [86] Chitosan Hepatocellular carcinoma [39] Diallyl isophthalate Liver cancer [87] Gelatin Osteosarcoma [20] Gelatin Hepatocellular carcinoma [19] Gelatin, genipin, and sodium alginate composite Hepatocellular carcinoma [38] Liquid metals Hepatocellular carcinoma [88] Methacrylated gelatin Hepatocellular carcinoma [48] PLGA Breast ca...…”