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....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 complications.展开更多
基金supported financially by the National Natural Science Foundation of China(No.81673363).
文摘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 complications.
