Enhanced lymphatic delivery of nanomicelles encapsulating CXCR4-recognizing peptide and doxorubicin for the treatment of breast cancer

Abstract Lymph node metastases in cancer patients are associated with high aggressiveness, poor prognosis, and short survival time. The chemokine receptor 4 (CXCR4)/stroma derived factor 1α (CXCL12) biological axis plays a critical role in the spread of cancer cells. Designing effective delivery systems that can successfully deliver CXCR4 antagonists to lymph nodes, which are rich in CXCR4-overexpressing cancer cells, for controlling cancer metastasis remain challenging. In this study, we demonstrated that such a challenge may be alleviated by developing nanometer-sized polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles for the co-delivery of the CXCR4 antagonistic peptide E5 and doxorubicin (M-E5-Dox). This nanomicelle platform enables the preferential accumulation of cargos into lymph nodes and thus can better inhibit cancer metastasis and enhance antitumor efficacy than either free drugs or single drug-loaded micelles in breast cancer-bearing mouse models. Hence, M-E5-Dox is expected to be a potential therapeutic agent that would improve the clinical benefits of breast cancer therapy and treatment of various CXCR4-overexpressing malignancies.