Fibronectin-targeted dual-acting micelles for combination therapy of metastatic breast cancer

Zhuoran Gong,Min Chen,Zhifei Dai,Xiuli Yue,Qiushi Ren

doi:10.1038/s41392-019-0104-3

Abstract

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.

Highlights

Nowadays, breast cancer has become one of the highly risky cancers threatening women's lives with high incidence
In summary, we have successfully developed a promising antimetastatic therapy for inhibiting breast cancer metastatic tumor invasion by assembling targeted micelles functionalized with CREKA peptide that could codeliver doxorubicin and vinorelbine (C-DVM)
The good stability and tolerability of CDVM could be used as a blueprint for the development of other agents for clinical use

Summary

Introduction

Breast cancer has become one of the highly risky cancers threatening women's lives with high incidence. Of breast cancer patients are diagnosed at stage IV, and the survival rate is less than 30%.1. Traditional chemotherapeutics is the standard clinic treatment of stage IV breast cancer, whereas the chemotherapeutic agents have deficiencies in long-term prognosis.[5] As the first choice for the treatment of cancers,[6] chemotherapy agents generally suffer low delivery efficiency to the tumor site with significant variation among different patients.[7] That is because of the resistance of metastatic site leading to low-efficiency therapeutic effect exists in cytotoxic agents, which cannot be delivered to metastatic sites precisely.[8,9] advances in breast cancer treatment require new platforms that can shrink the primary tumor, and target metastases by targeted drug delivery

Methods

Results

Conclusion