Zhu Chenxu, Li Chuang, Du Yibo, Chen Shi, Liu Xingliang, Liu Lixin, Chen Yongming
School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China.
College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China.
ACS Appl Mater Interfaces. 2025 Mar 12;17(10):15208-15219. doi: 10.1021/acsami.5c00670. Epub 2025 Feb 25.
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.
中性粒细胞胞外陷阱（NETs）通过与癌细胞表面的跨膜蛋白CCDC25相互作用搭载肿瘤细胞，从而诱导肿瘤转移。最近，我们应用带正电荷的聚氨基酸来中和带负电荷的NET-DNA，并在多种转移模型上证实其可抑制肿瘤转移。为了阐明聚合物结构对性能的具体影响，在此我们精确合成了一系列具有特定数量精氨酸（R）和甘氨酸（G）的阳离子寡肽。与R3和R3G6相比，寡肽R5、R7、R9和R5G4表现出更好的结合亲和力和更低的细胞毒性。通过下拉实验可知，由于在NETs中比髓过氧化物酶（MPO）和瓜氨酸化组蛋白H3（H3Cit）具有更强的竞争相互作用，寡聚精氨酸R5、R7和R9可抑制CCDC25与NET-DNA的相互作用。随后在三阴性乳腺癌（TNBC）小鼠模型中对细胞迁移和肿瘤转移的抑制作用表明，R5、R7和R9能有效阻止肿瘤细胞转移至肝脏和肺。寡聚精氨酸在肝脏和肺中的分布减少了NETs的积累，进一步证实了这一点。因此，在本研究中，我们筛选出了具有精确单元数量的寡聚精氨酸，以抑制TNBC向远处器官的转移，这可能有助于降低因肿瘤转移导致的死亡率。寡聚精氨酸因其低细胞毒性，代表了转移性疾病临床治疗的一项重大进展。
