Chemo–immunotherapy for chemo-resistance and metastasis of triple-negative breast cancer by combination of iron-oxide nanoparticles and dual-targeting doxorubicin liposomes  

作　　者：Heping Hu Lijia Yu Zhao Ding Jinsong Ding Yiguo Hu Zongning Yin 

机构地区：[1]Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China [2]Sichuan Huiyu Seacross Medical Technology Co.,Ltd.,Chengdu 610031,China [3]Sichuan Huiyu Pharmaceutical Co.,Ltd.,Neijiang 641000,China [4]Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410013,China [5]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,and Collaborative Innovation Center for Biotherapy,Chengdu 610044,China

出　　处：《Chinese Chemical Letters》2023年第10期76-81,共6页中国化学快报（英文版）

基　　金：supported financially by the National Natural Science Foundation of China(No.81673363).

摘　　要：Triple-negative breast cancer(TNBC)lacks specific regimens for targeted therapy.Repeat chemotherapy promotes the evolution of TNBC into highly chemo-resistant tumors that metastasize to multiple organs simultaneously.Herein,polyacrylic acid-coated ultrasmall superparamagnetic iron-oxide nanoparticles(PAA@IONs)and dual-targeting doxorubicin liposomes achieved chemo–immunotherapy through intermittent administration.They inhibited tumor-drug resistance and multiorgan-specific metastasis significantly by targeting tumors and the microenvironment.We deciphered an immunosuppressive pre-metastatic niche and discovered that PAA@IONs could target tumors,tumor-draining lymph nodes(TDLNs),the liver,bone,and lungs.They promoted the polarization of macrophages into M1 macrophages in these organs and tissues.This action remodeled the immunosuppressive microenvironment and induced a sustained immune response,thereby reducing organ-specific metastasis.Overcoming the disadvantages of doxorubicin-induced cardiotoxicity as well as low tumor specificity,dual peptide-modified liposomes could target CD206 and CD13 simultaneously,and reverse chemo-resistance.These properties resulted in a significant decrease in the numbers of myeloid-derived suppressor cells(MDSCs)and cancer stem cells(CSCs)in the liver,lungs,and bone,thereby reducing protein expression of Ki-67 in TDLNs,and dramatically increasing the number of cluster of differentiation(CD)8+T cells and CD8+T cell/T-regulatory-cell ratio in tumors and TDLNs(P<0.0001).Compared with the control(P<0.05 and P<0.01,respectively)or free drug(P<0.0001 and P<0.01,respectively),multi-organ metastases were suppressed significantly,tumor-growth rate reduced,and survival prolonged.Our drug-delivery system overcame TNBC chemo-resistance and inhibited multiorgan-specific metastases.It circumvents the lack of effective therapeutic targets,the problem of patient selection due to a low mutation rate,and can simultaneously offer the possibility of avoiding surgery and considerable postoperative com

关 键 词：Multidrug resistance Multiorgan-specific metastases Immunogenic cell death Intermittent dosing Immunosuppressive tumor microenvironment Tumor-associated macrophages 

分 类 号：R737.9[医药卫生—肿瘤] TB383.1[医药卫生—临床医学]