School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China.
School of Pharmacy, Jilin University, Changchun 130021, Jilin, PR China.
Int J Pharm. 2023 Nov 5;646:123500. doi: 10.1016/j.ijpharm.2023.123500. Epub 2023 Oct 10.
As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.
作为唯一经美国食品和药物管理局 (FDA) 批准用于治疗急性髓细胞白血病 (AML) 的双重包封脂质体注射剂，CPX-351 在临床疗效方面优于标准化疗治疗“DA 7+3”。尽管近年来对双重载药脂质体的研究有所增加，但对其制备方法的关注较少，而制备方法会影响其质量、疗效和安全性。本研究探讨了各种制备工艺来制备阿糖胞苷/柔红霉素共载脂质体（Cyt/Daun 脂质体），最终确定了两种方法：顺序加载法、薄膜水化-挤出-铜离子梯度法和同时包封技术、铜离子梯度-浓度梯度法。不同的制备方法导致不同的粒径和包封效率；上述两种制备工艺生成的双重载药脂质体具有相似的理化性质。由于在纯化前具有更高的包封效率，因此选择顺序包封技术用于后续研究；制备的 Cyt/Daun 脂质体具有小而均匀的粒径（108.6±1.02nm，多分散指数（PDI）0.139±0.01）、负电荷（-(60.2±1.15)mV）、高药物包封效率（Cyt 88.2±0.24%，Duan 94.2±0.45%）和良好的血浆稳定性。为了提高其储存稳定性，将 Cyt/Daun 脂质体在蔗糖-棉子糖（质量比 7:3；糖脂比 4:1，w/w）作为冻干保护剂的条件下进行冷冻干燥（-40°C 4 小时，保持 130 分钟，干燥 1200 分钟）。冻干脂质体为紫色块状物，重新溶解后粒径和包封效率无明显变化，具有良好的储存稳定性。药代动力学和组织分布研究表明，Cyt/Daun 脂质体可实现长循环，并在 24 小时内保持药物的协同比例，增加药物在肿瘤部位的蓄积。此外，体外/体内药效学研究证实了其良好的抗肿瘤活性和安全性。
