Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Department of Biological Sciences, College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Int J Mol Sci. 2023 Mar 8;24(6):5204. doi: 10.3390/ijms24065204.
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 IC 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.
恶性胸膜间皮瘤（MPM）是一种罕见且侵袭性的癌症，影响肺部的胸膜衬里。Celastrol（Cela）是一种五环三萜，作为抗氧化剂、抗炎剂、神经保护剂和抗癌剂，具有广阔的治疗潜力。在这项研究中，我们使用双乳液溶剂蒸发法开发了载有 Celastrol 的表面修饰聚乳酸-共-羟基乙酸（PLGA）微米颗粒（Cela MPs），用于治疗 MPM。优化后的 Cela MPs 表现出高包封效率（72.8±6.1%），具有皱缩的表面，平均几何直径约为 2 µm，空气动力学直径为 4.5±0.1 µm，表明其适合肺部给药。随后的释放研究表明，初始突释高达 59.9±2.9%，随后是持续释放。Cela MPs 的治疗效果在四种间皮瘤细胞系中进行了评估，其中 Cela MP 显著降低了 IC 值，而空白 MPs 对正常细胞没有毒性。此外，还进行了 3D 球体研究，其中 1.0 µM 的单次 Cela MP 剂量显著抑制了球体生长。Cela MP 还能够保留 Cela 的抗氧化活性，而机制研究表明它触发了自噬并诱导了细胞凋亡。因此，这些研究强调了 Cela 的抗间皮瘤活性，并表明 Cela MPs 是一种有前途的可吸入药物，可用于治疗 MPM。
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