Citation: Heping Hu, Lijia Yu, Zhao Ding, Jinsong Ding, Yiguo Hu, Zongning Yin. Chemo–immunotherapy for chemo-resistance and metastasis of triple-negative breast cancer by combination of iron-oxide nanoparticles and dual-targeting doxorubicin liposomes[J]. Chinese Chemical Letters, ;2023, 34(10): 108592. doi: 10.1016/j.cclet.2023.108592 shu

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

Heping Hu ^a ,
Lijia Yu ^b ,
Zhao Ding ^c ,
Jinsong Ding ^d ,
Yiguo Hu ^e ,
Zongning Yin ^{a, *,}

a.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
b.
Sichuan Huiyu Seacross Medical Technology Co., Ltd., Chengdu 610031, China
c.
Sichuan Huiyu Pharmaceutical Co., Ltd., Neijiang 641000, China
d.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
e.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610044, China

yzn@scu.edu.cn

Received Date: 5 February 2023
Revised Date: 13 May 2023
Accepted Date: 18 May 2023
Available Online: 19 May 2023

Figures(4)

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.
- Multidrug resistance,
- Multiorgan-specific metastases,
- Immunogenic cell death,
- Intermittent dosing,
- Immunosuppressive tumor microenvironment,
- Tumor-associated macrophages
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