Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
AAPS PharmSciTech. 2020 Nov 18;21(8):325. doi: 10.1208/s12249-020-01867-x.
Conventional combination chemotherapy often leads to unsatisfactory clinical outcomes due to the different distribution characteristics in vivo and the superimposed systemic toxicity of the drug cocktail. Co-encapsulated nano preparations have been gradually developed in recent years. In this work, cytarabine (Ara-C)/daunorubicin (DNR) liposomes were prepared by the pH gradient (ADL-pH) and Cu gradient (ADL-Cu) methods. Ara-C did not show significant release from either ADL-Cu or ADL-pH in vitro during 168 h, which related to its logP. Different drug-loading patterns showed different release characteristics of DNR due to the different existence forms, ADL-pH contains the citrate form, while in ADL-Cu, there is the Cu complex. To evaluate the release behavior, daunorubicin liposome (DL) and daunorubicin-Cu complex (DNR-Cu) were prepared. The addition of EDTA in the release medium significantly increased the release rate of DNR from DL-Cu, while lower pH accelerated DNR release from both DL-pH and DL-Cu. The PK confirmed that ADL-Cu and ADL-pH could prolong the drug circulation time, and ADL-Cu had a mean retention time 1.5 times that of ADL-pH. Furthermore, both liposomes allowed the two drugs to maintain a relatively constant plasma concentration ratio for a prolonged time. Cytotoxicity assays showed that Ara-C/DNR with a molar ratio of 5:1 and 3:1 exhibited an excellent synergistic effect, which was more obvious at 5:1. In vitro antitumor results revealed that ADL-Cu exhibited more cytotoxicity than ADL-pH. All factors tested in this work suggest the considerable potential of ADL-Cu and ADL-pH for anticancer treatment.
常规联合化疗由于药物混合物在体内分布特征不同和叠加的全身毒性，往往导致临床疗效不理想。近年来，共包封的纳米制剂逐渐得到发展。在这项工作中，通过 pH 梯度（ADL-pH）和 Cu 梯度（ADL-Cu）方法制备了阿糖胞苷（Ara-C）/柔红霉素（DNR）脂质体。在 168 小时内，Ara-C 没有从 ADL-Cu 或 ADL-pH 中明显释放，这与它的 logP 有关。由于存在形式不同，不同的载药模式显示出不同的 DNR 释放特征，ADL-pH 含有柠檬酸盐形式，而在 ADL-Cu 中，存在 Cu 配合物。为了评估释放行为，制备了柔红霉素脂质体（DL）和柔红霉素-Cu 配合物（DNR-Cu）。释放介质中 EDTA 的加入显著增加了 DNR 从 DL-Cu 中的释放率，而较低的 pH 加速了 DNR 从 DL-pH 和 DL-Cu 中的释放。药代动力学证实，ADL-Cu 和 ADL-pH 可以延长药物循环时间，ADL-Cu 的平均保留时间是 ADL-pH 的 1.5 倍。此外，两种脂质体都能使两种药物在较长时间内保持相对恒定的血浆浓度比。细胞毒性试验表明，摩尔比为 5:1 和 3:1 的 Ara-C/DNR 表现出优异的协同作用，在 5:1 时更为明显。体外抗肿瘤结果表明，ADL-Cu 比 ADL-pH 具有更强的细胞毒性。本工作中测试的所有因素都表明 ADL-Cu 和 ADL-pH 在抗癌治疗中具有相当大的潜力。
