The glycosaminoglycans (GAGs) on cell surfaces play significant roles during cancer development, and the heparanase activity is strongly implicated in the structural remodeling of the extracellular GAG matrix, potentially leading to tumour cell invasion. Polymer–protein/peptide conjugates are one of the most promising approaches for anticancer therapy due to their controllability, biocompatibility, and targeting properties. In this study, distinct and well-defined glycopolymer–peptide conjugates, mimicking the multivalent architecture found in GAGs, were synthesised for targeting and killing tumour cells. Regio-selectively sulphated galactosamine derivatives were chemically synthesised, and six GAGs-mimetic glycopolymers were generated by post-modification based on the ring-opening metathesis polymerization (ROMP). The glycopolymers with diverse galactosamine sulphation patterns showed significant inhibitory effects on heparanase. Glycopolymers decorated with 3,4,6-O-sulphated GalNAc exhibited the highest activities, inhibiting heparanase as well as tumour cell proliferation. We demonstrated that a novel glycopeptide mimetic, derived from end-functionalised conjugation of the iRGD peptide on the glycopolymer, could effectively enter HeLa cells and inhibit signalling pathways involved in tumour cell proliferation. These findings should promote the development of novel glycomimetics for specific tumour-targeted therapies.

中文翻译：

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末端官能化糖聚合物作为糖胺聚糖模拟物抑制HeLa细胞增殖

细胞表面的糖胺聚糖（GAG）在癌症发展过程中起着重要作用，乙酰肝素酶的活性与细胞外GAG基质的结构重塑密切相关，有可能导致肿瘤细胞侵袭。聚合物-蛋白质/肽结合物由于其可控性，生物相容性和靶向特性，是抗癌治疗最有前途的方法之一。在这项研究中，模仿GAG中发现的多价结构的独特且定义明确的糖聚合物-肽结合物被合成用于靶向和杀死肿瘤细胞。化学合成了区域选择性硫酸化的半乳糖胺衍生物，并基于开环易位聚合（ROMP）通过后修饰生成了6种GAGs模拟糖聚合物。具有多种半乳糖胺硫酸化模式的糖聚合物显示出对乙酰肝素酶的显着抑制作用。用3,4,6-装饰的糖共聚物O硫酸化的GalNAc表现出最高的活性，抑制乙酰肝素酶以及肿瘤细胞的增殖。我们证明了一种新的糖肽模拟物，其源自糖聚合物上iRGD肽的末端功能化偶联，可以有效进入HeLa细胞并抑制参与肿瘤细胞增殖的信号通路。这些发现应促进针对特定肿瘤靶向疗法的新型糖模拟物的开发。