Metwally Abdelkader A, Ganguly Samayita, Biomi Nora, Yao Mingyi, Elbayoumi Tamer
Department of Pharmaceutics, College of Pharmacy, Health Science Center (HSC), Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Abbasseya, Cairo 11566, Egypt.
Molecules. 2024 Mar 5;29(5):1155. doi: 10.3390/molecules29051155.
Anthracycline antibiotics, namely, doxorubicin (DOX) and daunorubicin, are among the most widely used anticancer therapies, yet are notoriously associated with severe myocardial damage due to oxidative stress and mitochondrial damage. Studies have indicated the strong pharmacological properties of Berberine (Brb) alkaloid, predominantly mediated via mitochondrial functions and nuclear networks. Despite the recent emphasis on Brb in clinical cardioprotective studies, pharmaceutical limitations hamper its clinical use. A nanoformulation for Brb was developed (mMic), incorporating a cationic lipid, oleylamine (OA), into the TPGS-mixed corona of PEGylated-phosphatidylethanolamine (PEG-PE) micelles. Cationic TPGS/PEG-PE mMic with superior Brb loading and stability markedly enhanced both intracellular and mitochondria-tropic Brb activities in cardiovascular muscle cells. Sub-lethal doses of Brb via cationic OA/TPGS mMic, as a DOX co-treatment, resulted in significant mitochondrial apoptosis suppression. In combination with an intense DOX challenge (up to ~50 µM), mitochondria-protective Brb-OA/TPGS mMic showed a significant 24 h recovery of cell viability ( ≤ 0.05-0.01). Mechanistically, the significant relative reduction in apoptotic caspase-9 and elevation of antiapoptotic Bcl-2 seem to mediate the cardioprotective role of Brb-OA/TPGS mMic against DOX. Our report aims to demonstrate the great potential of cationic OA/TPGS-mMic to selectively enhance the protective mitohormetic effect of Brb to mitigate DOX cardiotoxicity.
蒽环类抗生素，即阿霉素（DOX）和柔红霉素，是应用最广泛的抗癌疗法之一，但因氧化应激和线粒体损伤而与严重的心肌损伤密切相关。研究表明，黄连素（Brb）生物碱具有强大的药理特性，主要通过线粒体功能和核网络介导。尽管最近临床心脏保护研究中对Brb的关注度有所提高，但其药物局限性阻碍了其临床应用。已开发出一种Brb的纳米制剂（mMic），将阳离子脂质油胺（OA）纳入聚乙二醇化磷脂酰乙醇胺（PEG-PE）胶束的TPGS混合冠层中。具有优异Brb负载量和稳定性的阳离子TPGS/PEG-PE mMic显著增强了心血管肌肉细胞内的Brb活性和线粒体靶向性Brb活性。作为DOX联合治疗，通过阳离子OA/TPGS mMic给予亚致死剂量的Brb可显著抑制线粒体凋亡。与高强度的DOX刺激（高达约50μM）联合使用时，具有线粒体保护作用的Brb-OA/TPGS mMic可使细胞活力在24小时内显著恢复（≤0.05 - 0.01）。从机制上讲，凋亡半胱天冬酶-9的显著相对降低和抗凋亡蛋白Bcl-2的升高似乎介导了Brb-OA/TPGS mMic对DOX的心脏保护作用。我们的报告旨在证明阳离子OA/TPGS-mMic在选择性增强Brb的保护性线粒体应激效应以减轻DOX心脏毒性方面具有巨大潜力。
