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

• Published in: Journal of controlled release Vol. 318; pp. 124 - 135
• Main Authors: Luo, Lei, Xu, Fanshu, Peng, Huilan, Luo, Yonghuang, Tian, Xiaohe, Battaglia, Giuseppe, Zhang, Hu, Gong, Qiyong, Gu, Zhongwei, Luo, Kui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020
• Subjects: Breast metastasis; Controlled release; Drug delivery; Polymeric prodrug; Stimuli-responsive; Stimuli-responsive; Drug delivery; Breast metastasis; Polymeric prodrug; Controlled release
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2019.12.017

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. A cathepsin B/pH dual-sensitive block copolymer with doxorubicin was prepared to load nifuroxazide. The stimuli-responsive co-prodrug-loaded micelles showed great potential safe and efficient nanomedicine against breast cancer metastasis. [Display omitted]