Neutrophil extracellular traps (NETs) induce tumor metastasis by riding tumor cells through interaction via the transmembrane protein CCDC25 on the surface of cancer cells. Recently, we applied positively charged polyamino acids to neutralize negatively charged NET-DNA and inhibit tumor metastasis as approved on several metastasis models. To elucidate the exact polymer structures on performance, herein, we precisely synthesized a series of cationic oligopeptides with defined numbers of arginine (R) and glycine (G). The oligopeptides R5, R7, R9, and R5G4 showed much better binding affinity and lower cytotoxicity than R3 and R3G6. From the pull-down assay, the oligoarginines, R5, R7, and R9, inhibited CCDC25 interaction with NET-DNA because of stronger competitive interaction than myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit) in NETs. The subsequent inhibition of cell migration and tumor metastasis in triple-negative breast cancer (TNBC) mouse models demonstrated that R5, R7, and R9 efficiently prevented tumor cell metastasis to the liver and lung. This was corroborated by the distribution of oligoarginines in the liver and lung, which reduced NETs accumulation. Thus, in this study, we screened out oligoarginines with a precise number of units to inhibit TNBC metastasis to distant organs, which may benefit in the decreasing mortality rate because of tumor metastasis. With their low cytotoxicity, oligoarginines represent a major advancement for the clinical treatment of metastatic diseases.
Cancer metastasis that is resistant to conventional therapies has become a major cause of patient death. Recent reports indicate that the neutrophil extracellular trap (NET) is closely associated with cancer distant metastases, and the cell-free DNA of NETs has been identified as the ligand of the transmembrane protein CCDC25 of cancer cells, acting as a chemokine to induce cancer cell migration to distant organs. In this work, we present the poly(aspartic acid) based-cationic materials to interfere with the interaction between NET-DNA and CCDC25, and furthermore to inhibit NET-DNA-mediated cancer cell chemotaxis and migration. Because of a stronger binding affinity to DNA and favorable retention in the liver, nanoparticulate poly(aspartic acid) derivatives (cANP) efficiently reduce the level of hepatic NET-DNA infiltration, leading to a significant suppression of cancer metastases in mice and several human metastatic models. Moreover, the cANP exhibits no toxicity to organs of animals during the entire treatment. Thus, this work suggests a strategy for controlling cancer metastases, which will benefit patients in clinics.
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