Stimuli-responsive polymeric prodrug-based nanomedicine delivering nifuroxazide and doxorubicin against primary breast cancer and pulmonary metastasis

JOURNAL OF CONTROLLED RELEASE

卷:318

Article

Luo, Lei¹  Xu, Fanshu¹  Peng, Huilan¹  Luo, Yonghuang¹  Tian, Xiaohe³  Battaglia, Giuseppe^1,5  Zhang, Hu⁴  Gong, Qiyong²  Gu, Zhongwei²  Luo, Kui² 

[1] Southwest Univ, Coll Pharmaceut Sci, Minist Educ, Key Lab Luminescent & Real Time Analyt Chem, Chongqing 400715, Peoples R China

[2] Sichuan Univ, Funct & Mol Imaging Key Lab Sichuan Prov, West China Hosp,Dept Radiol, Huaxi MR Res Ctr HMRRC,Natl Engn Res Ctr Biomat, Chengdu 610041, Peoples R China

[3] Anhui Univ, Dept Chem, Key Lab Funct Inorgan Mat Chem Anhui Prov, Hefei 230039, Peoples R China

[4] Keck Grad Inst, Amgen Bioproc Ctr, Claremont, CA 91711 USA

[5] UCL, Dept Chem Engn, Dept Chem, London, England

关键词: Polymeric prodrug;    Stimuli-responsive;    Drug delivery;    Breast metastasis;    Controlled release;   

DOI  :  10.1016/j.jconrel.2019.12.017

来源: Elsevier

【 摘 要 】

Functionalized drug delivery systems against malignant lung metastasis of breast cancer have been extensively studied, while metastasis remains a challenging issue. We propose a new strategy to achieve eradication of primary breast cancer cells and inhibition of pulmonary metastasis. A cathepsin B/pH dual-sensitive block copolymer with a molecular weight of 92 kDa was synthesized to conjugate with doxorubicin (DOX). The copolymer-DOX was further loaded with nifuroxazide (NFX) to self-assemble co-prodrug-loaded micelles (CLM). CLM displayed a drug release pattern in response to pH/enzyme dual stimuli and was enzymatically biodegradable. CLM was demonstrated to reduce viability and inhibit migration and invasion of 4T1 murine breast cancer cells in vitro. After i.v. injection of CLM, its nanoscale size and stimuli-responsiveness facilitated delivery of drugs to the tumor site in mice. Enhanced anti-tumor efficacy and great anti-metastatic effects were found in both orthotropic and lung metastasis 4T1 breast cancer mice models. Meanwhile, histological immunofluorescence and immunohistochemical analyses revealed a high level of apoptosis, suppressed expression of matrix metalloproteinases and reduction in MDSCs infiltration, and all these contributed to inhibit pulmonary metastasis. CLM may be explored as a potential nanomedicine against breast cancer metastasis.

【 授权许可】

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