Abstract
Cancer is the leading cause of death worldwide, and metastasis is the main attribute to cancer death. CXCR4 and its natural ligand CXCL12 have been known to play a critical role in tumorigenesis, angiogenesis and metastasis. Therefore, designing a new CXCR4 antagonist to prevent tumor metastasis will be of great significance. Herein, a novel chemically synthesized peptide (E5) that has an ability to target CXCR4/CXCL12 axis was loaded in micelle glycol-phosphatidylethanolamine (PEG-PE) block copolymer to form micelle-encapsulated E5 (M-E5). We demonstrated that M-E5 exhibited higher affinity for CXCR4-overexpressing MCF-7 and HepG2 tumor cells as compared to free E5, and efficiently inhibited the tumor cells migration. Mechanistic studies implied that PEG-PE micelle can encapsulate E5 and improve E5 targeting efficiency for CXCR4 by accumulating E5 on the tumor cell membrane. Furthermore, through encapsulation of chemotherapeutic drug doxorubicin (Dox) in PEG-PE micelle, we proved that PEG-PE micelle could serve as a co-carrier for both E5 and Dox (M-E5-Dox). M-E5 enhanced the efficiency of Dox by down-regulating the phosphorylation level of Akt, Erk and p38/MAPK proteins. In conclusion, PEG-PE micelle demonstrated a promising delivery system for E5, and M-E5 is expected to be a potential therapeutic agent that will help to improve the clinical benefits in current therapies used for solid tumors.
Highlights
Tumor metastasis is one of the leading cause of death in 90% of patients suffering from malignant tumor [1,2]
We have investigated the interaction of two water-soluble anticancer drugs E5 and Dox with poly(ethylene glycol)-phosphatidylethanolamine (PEG-PE) micelles
We have demonstrated that PEG-PE micelle could encapsulate a peptide antagonist E5 and improve E5 targeting efficiency for CXCR4 by accumulating E5 on the cell membrane
Summary
Tumor metastasis is one of the leading cause of death in 90% of patients suffering from malignant tumor [1,2]. Metastasis can be well described in two-phase, tumor metastasis starts with the migration of tumor cells from primary tumor to a distant organ of potential metastasis (first phase). Later on tumor cells proliferate within a micrometastasis that leads to the formation of a macroscopic metastatic lesion at the distant site (second phase) [3].
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