Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages  

作　　者：Ting-ting Lin Wei Xiong Gui-hua Chen Yang He Li Long Xin-fu Gao Jia-lin Zhou Wen-wen Lv Yong-zhuo Huang 

机构地区：[1]Department of Pharmacy,Binzhou Medical University Hospital,Binzhou,256603,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]Artemisinin Research Center,Guangzhou University of Chinese Medicine,Guangzhou,510450,China [4]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528437,China [5]NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients,Shanghai,201203,China

出　　处：《Acta Pharmacologica Sinica》2024年第4期867-878,共12页中国药理学报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2021YFC2400600,2021YFE0103100);NFSC(81925035);Department of Science and Technology of Guangdong Province(High-level new R&D institute 2019B090904008,High-level Innovative Research Institute 2021B0909050003);the Scientific and Technological Innovation Leading Talent Project in Zhongshan City(LJ2021001);the Scientific Research and Innovation Team Project in Zhongshan City(CXTD2022011);and Research Foundation of Binzhou Medical University(BY2019KJ03).

摘　　要：Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

关 键 词：osimertinib resistance targeted drug delivery liposomes PANOBINOSTAT tumor-associated macrophage combination therapy 

分 类 号：R730.5[医药卫生—肿瘤]