Fibronectin-targeted dual-acting micelles for combination therapy of metastatic breast cancer
Fibronectin-targeted dual-acting micelles for combination therapy of metastatic breast cancer
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DOI：
10.1038/s41392-019-0104-3
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发表时间：
2020-02-07
影响因子：
39.3
通讯作者：
Dai, Zhifei
中科院分区：
文献类型：
--
作者：
Gong, Zhuoran;Chen, Min;Dai, Zhifei
第四期乳腺癌具有很高的侵袭风险，经常发展为远处器官的转移，特别是肺部，这可能威胁妇女的生命。因此，开发更先进的治疗方法，可以有效地靶向转移灶是至关重要的。在这项研究中，我们建立了一种双重作用的治疗策略，使用具有高稳定性的胶束功能化的纤连蛋白靶向CREKA肽封装在水中的两种微溶性化疗剂，阿霉素（D）和长春瑞滨（V），我们称之为C-DVM。我们发现小的C-DVM胶束可以有效地将药物共递送到4 T1细胞中并破坏微管结构。C-DVM还表现出强大的根除和抑制4 T1细胞侵袭的能力。此外，体内药代动力学研究表明，C-DVM延长了药物循环半衰期，并导致24 h后肺转移灶中药物富集增加。此外，双作用C-DVM治疗导致90%的转移灶发展抑制和转移灶侵袭减少。C-DVM可能被用作转移的靶向治疗，并代表了一种比传统化疗更高的治疗效果的新方法，可用于未来的IV期乳腺癌。
Stage IV breast cancer, which has a high risk of invasion, often develops into metastases in distant organs, especially in the lung, and this could threaten the lives of women. Thus, the development of more advanced therapeutics that can efficiently target metastatic foci is crucial. In this study, we built an dual-acting therapeutic strategy using micelles with high stability functionalized with fibronectin-targeting CREKA peptides encapsulating two slightly soluble chemotherapy agents in water, doxorubicin (D) and vinorelbine (V), which we termed C-DVM. We found that small C-DVM micelles could efficiently codeliver drugs into 4T1 cells and disrupt microtubule structures. C-DVM also exhibited a powerful ability to eradicate and inhibit invasion of 4T1 cells. Moreover, an in vivo pharmacokinetics study showed that C-DVM increased the drug circulation half-life and led to increased enrichment of drugs in lung metastatic foci after 24 h. Moreover, dual-acting C-DVM treatment led to 90% inhibition of metastatic foci development and reduced invasion of metastases. C-DVM could potentially be used as a targeted treatment for metastasis and represents a new approach with higher therapeutic efficacy than conventional chemotherapy for stage IV breast cancer that could be used in the future.