阿法替尼
表皮生长因子受体
西妥昔单抗
药理学
体内
医学
肺癌
内化
酪氨酸激酶
癌症研究
化学
单克隆抗体
免疫学
受体
埃罗替尼
内科学
抗体
生物
生物技术
作者
Xiaoyan Lu,Sha Li,Meishan Han,Xiucheng Yang,Kaoxiang Sun,Hongbo Wang,Hongjie Mu,Yuan Du,Aiping Wang,Ling Ni,Chunyan Zhang
标识
DOI:10.1016/j.ijpharm.2019.02.001
摘要
Afatinib, a selective and irreversible inhibitor of tyrosine kinase, was approved for the treatment of advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) overexpression in 2013. Cetuximab (CTX), an anti-EGFR monoclonal antibody, is co-administered with afatinib to improve efficacy. Unfortunately, dose-related adverse reactions caused by combination therapy have affected patient compliance, and have resulted in treatment discontinuation in severe cases. In the present study, afatinib was encapsulated in "liposomes" (LPs) to achieve longer circulation in the blood and an enhanced permeability-and-retention effect in tumors. Concomitantly, CTX was designed to bind to drug-loaded LPs to form "immuno-LPs" for tumor-cell selectivity and therapeutic activity. In vitro, the cellular internalization rate of immuno-LPs was significantly higher than that of LPs (p < 0.05). In vivo, a markedly increased area under the curve and prolonged terminal half-life were detected in rats injected with the two LP formulations, indicating that LP encapsulation protected afatinib from binding to hemoglobin to control the risk of idiosyncratic drug reactions. Compared with free afatinib and LPs, immuno-LPs exhibited strongly enhanced drug delivery and antitumor efficacy in an NSCLC xenograft model, with stronger tumor selectivity and potentially fewer side-effects. Hence, EGFR-targeting immuno-LPs appear to be promising for NSCLC treatment.
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