Department of Biomaterials Science and Technology, University of Twente, Enschede, Drienerlolaan 5, 7522 NB Enschede, The Netherlands.
Department of Pharmacy, National University of Singapore, Science Drive 2, 117543, Singapore; Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
J Control Release. 2017 Feb 10;247:127-133. doi: 10.1016/j.jconrel.2016.12.042. Epub 2017 Jan 5.
Inflammation is a known mediator of adverse ventricular remodeling after myocardial infarction (MI) that may lead to reduction of ejection fraction and subsequent heart failure. Berberine is a isoquinoline quarternary alkaloid from plants that has been associated with anti-inflammatory, anti-oxidative, and cardioprotective properties. Its poor solubility in aqueous buffers and its short half-life in the circulation upon injection, however, have been hampering the extensive usage of this natural product. We hypothesized that encapsulation of berberine into long circulating liposomes could improve its therapeutic availability and efficacy by protecting cardiac function against MI in vivo. Berberine-loaded liposomes were prepared by ethanol injection and characterized. They contained 0.3mg/mL of the drug and were 0.11μm in diameter. Subsequently they were tested for IL-6 secretion inhibition in RAW 264.7 macrophages and for cardiac function protection against adverse remodeling after MI in C57BL/6J mice. In vitro, free berberine significantly inhibited IL-6 secretion (IC=10.4μM), whereas encapsulated berberine did not as it was not released from the formulation in the time frame of the in vitro study. In vivo, berberine-loaded liposomes significantly preserved the cardiac ejection fraction at day 28 after MI by 64% as compared to control liposomes and free berberine. In conclusion, liposomal encapsulation enhanced the solubility of berberine in buffer and preserves ejection fraction after MI. This shows that delivery of berberine-loaded liposomes significantly improves its therapeutic availability and identifies berberine-loaded liposomes as potential treatment of adverse remodeling after MI.
炎症是心肌梗死后不良心室重构的已知介质，可能导致射血分数降低和随后的心衰。小檗碱是一种从植物中提取的异喹啉季铵生物碱，具有抗炎、抗氧化和心脏保护作用。然而，其在水缓冲液中的溶解度差，注射后在循环中的半衰期短，一直阻碍着这种天然产物的广泛应用。我们假设将小檗碱包封在长循环脂质体中，可以通过保护心脏功能来改善其治疗效果，从而防止体内心肌梗死后的不良重构。通过乙醇注入法制备载小檗碱的脂质体，并对其进行了表征。脂质体中含有 0.3mg/mL 的药物，直径为 0.11μm。随后，我们在 RAW 264.7 巨噬细胞中测试了它们对白细胞介素-6（IL-6）分泌的抑制作用，并在 C57BL/6J 小鼠中测试了它们对心肌梗死后不良重构的心脏功能保护作用。在体外，游离小檗碱能显著抑制 IL-6 的分泌（IC=10.4μM），而包封的小檗碱则没有，因为它在体外研究的时间范围内没有从制剂中释放出来。在体内，与对照脂质体和游离小檗碱相比，载小檗碱脂质体可使心肌梗死后 28 天的心脏射血分数显著提高 64%。结论：脂质体包封提高了小檗碱在缓冲液中的溶解度，并保持了心肌梗死后的射血分数。这表明，载小檗碱脂质体的递送显著提高了其治疗效果，并确定了载小檗碱脂质体是治疗心肌梗死后不良重构的潜在方法。
