Investigation of the antitumor activity and toxicity of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in a murine breast cancer animal model
Investigation of the antitumor activity and toxicity of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in a murine breast cancer animal model
复制标题
DOI：
10.1016/j.biopha.2018.11.011
复制
发表时间：
2019-01-01
影响因子：
7.5
通讯作者：
Oliveira, Monica Cristina
中科院分区：
文献类型：
--
作者：
Franco, Marina Santiago;Roque, Marjorie Coimbra;Oliveira, Monica Cristina
联合紫杉醇（PTX）与阿霉素（DXR）是乳腺癌（BC）治疗的主要化疗策略之一。尽管这种组合的反应率很高，但由于PTX与DXR及其代谢物阿霉素之间的药代动力学相互作用，它呈现出心脏毒性协同作用。减少心脏毒性的主要策略之一是延长DXR和PTX给药之间的时间间隔。然而，先前有研究表明，与顺序给药相比，它们的联合给药效果更好。在本研究中，我们研究了PTX:DXR的不同摩尔比组合（10:1、1:1和1:10）对4T1小鼠乳腺癌细胞系的作用，并得出PTX浓度高于DXR对组合没有任何好处。因此，我们分别以1:10的摩尔比获得了PTX和DXR共包封的长循环、促聚变的脂质体制剂（LCFL-PTX/DXR），该制剂保持了联合用药的体外生物活性。研究了该制剂对4T1乳腺肿瘤Balb/c小鼠的抗肿瘤活性和毒性，并与游离PTX、游离DXR、游离PTX与DXR按1:10摩尔比混合治疗进行了比较。脂质体中游离PTX:DXR组和共包封PTX:DXR组的肿瘤抑制率分别为66.87和66.52% (P < 0.05)，高于对照组。LCFL-PTX/DXR治疗的巨大优势是其改善的心脏毒性特征。虽然用游离PTX:DXR联合治疗的所有动物的心脏都观察到变性，但用LCFL-PTX/DXR治疗的动物没有观察到心脏毒性的迹象。因此，LCFL-PTX/DXR可实现PTX和DXR的联合给药，可能被认为对乳腺癌治疗有价值。
To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for this combination, it presents a cardiotoxic synergism, attributed to pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol. One of the main strategies to minimize the cardiotoxicity of the combination is to extend the interval of time between DXR and PTX administration. However, it has been previously suggested that their co-administration leads to better efficacy compared to their sequential administration. In the present study, we investigated different molar ratio combinations of PTX:DXR (10:1; 1:1, and 1:10) against the 4T1 murine breast cancer cell line and concluded that there is no benefit of enhancing PTX concentration above that of DXR on the combination. Therefore, we obtained a long-circulating and fusogenic liposomal formulation co-encapsulating PTX and DXR (LCFL-PTX/DXR) at a molar ratio of 1:10, respectively, which maintained the in vitro biological activity of the combination. This formulation was investigated for its antitumor activity and toxicity in Balb/c mice bearing 4T1 breast tumor, and compared to treatments with free PTX, free DXR, and the mixture of free PTX:DXR at 1:10 molar ratio. The higher tumor inhibition ratios were observed for the treatments with free and co-encapsulated PTX:DXR in liposomes (66.87 and 66.52%, respectively, P > 0.05) as compared to the control. The great advantage of the treatment with LCFL-PTX/DXR was its improved cardiac toxicity profile. While degeneration was observed in the hearts of all animals treated with the free PTX:DXR combination, no signs of cardiac toxicity were observed for animals treated with the LCFL-PTX/DXR. Thus, LCFL-PTX/DXR enables the co-administration of PTX and DXR, and might be considered valuable for breast cancer management.