Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine  

作　　者：Jianxin Wang Megan N.Dang Emily S.Day 

机构地区：[1]Department of Biomedical Engineering,University of Delaware,Newark,DE,19716,USA [2]Department of Materials Science and Engineering,University of Delaware,Newark,DE,19716,USA [3]Helen F.Graham Cancer Center&Research Institute,Newark,DE,19713,USA

出　　处：《Nano Research》2020年第6期1693-1703,共11页纳米研究（英文版）

基　　金：This work was supported with funding from the National Institutes of Health(NIH)under grant numbers R35GM119659 and R01CA211925。

摘　　要：Nano Research volume 13,pages1693–1703(2020)Cite this article 137 Accesses 6 Altmetric Metrics details Abstract Despite improvements in our understanding of the biology behind triple-negative breast cancer(TNBC),it remains a devastating disease due to lack of an effective targeted therapy.Inhibiting Wnt signaling is a promising strategy to combat TNBC because Wnt signaling drives TNBC progression,chemoresistance,and stemness.However,Wnt inhibition can lead to upregulation of autophagy,which confers therapeutic resistance.This provides an opportunity for combination therapy,as autophagy inhibitors applied concurrently with Wnt inhibitors could increase treatment efficacy.Here,we applied the autophagy inhibitor chloroquine(CQ)to TNBC cells in combination with Frizzled7 antibody-coated nanoshells(FZD7-NS)that suppress Wnt signaling by blocking Wnt ligand/FZD7 receptor interactions,and evaluated this dual treatment in vitro.We found that FZD7-NS can inhibit Axin2 and CyclinD1,two targets of canonical Wnt signaling,and increase the expression of LC3,an autophagy marker.When FZD7-NS and CQ are applied together,they reduce the expression of several stemness genes in TNBC cells,leading to inhibition of TNBC cell migration and self-renewal.Notably,co-delivery of FZD7-NS and CQ is more effective than either therapy alone or the combination of CQ with free FZD7 antibodies.This demonstrates that the nanocarrier design is important to its therapeutic utility.Overall,these findings indicate that combined regulation of Wnt signaling and autophagy by FZD7-NS and CQ is a promising strategy to combat TNBC.

关 键 词：NANOMEDICINE nanoparticles combination therapy antibody delivery cancer stem cells 

分 类 号：R737.9[医药卫生—肿瘤]