Rationale: Use of traditional anticancer chemotherapeutics has been hindered by the multifactorial nature of multi-drug resistance (MDR) development and metastasis. Recently, cationic polycarbonates were reported as novel unconventional anticancer agents that mitigated MDR and inhibited metastasis. The aim of this study is to explore structure-anticancer activity relationship. Specifically, a series of cationic guanidinium-based random copolymers of varying hydrophobicity was synthesized with a narrow polydispersity (Ð = 1.12-1.27) via organocatalytic ring-opening polymerization (OROP) of functional cyclic carbonate monomers, and evaluated for anticancer activity, killing kinetics, degradability and functional mechanism. Methods: Linear, branched and aromatic hydrophobic side chain units, such as ethyl, benzyl, butyl, isobutyl and hexyl moieties were explored as comonomer units for modulating anticancer activity. As hydrophobicity/hydrophilicity balance of the polymers determines their anticancer efficacy, the feed ratio between the two monomers was varied to tune their hydrophobicity. Results: Notably, incorporating the hexyl moiety greatly enhanced anticancer efficiency and killing kinetics on cancer cells. Degradation studies showed that the polymers degraded completely within 4-6 days. Flow cytometry and lactate dehydrogenase (LDH) release analyses demonstrated that anticancer mechanism of the copolymers containing a hydrophobic co-monomer was concentration dependent, apoptosis at IC50, and both apoptosis and necrosis at 2 × IC50. In contrast, the homopolymer without a hydrophobic comonomer killed cancer cells predominantly via apoptotic mechanism. Conclusion: The hydrophobicity of the polymers played an important role in anticancer efficacy, killing kinetics and anticancer mechanism. This study provides valuable insights into designing novel anticancer agents utilizing polymers.

中文翻译：

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通过改变疏水单体的结构和组成来阐明胍官能化两亲性无规共聚物的抗癌活性。


理由：传统抗癌化疗药物的使用受到多药耐药性 (MDR) 发展和转移的多因素性质的阻碍。最近，据报道，阳离子聚碳酸酯是一种新型非常规抗癌剂，可以减轻多药耐药并抑制转移。本研究的目的是探讨结构与抗癌活性的关系。具体来说，通过功能性环状碳酸酯单体的有机催化开环聚合（OROP）合成了一系列具有不同疏水性的、具有窄多分散性（Ð = 1.12-1.27）的阳离子胍基无规共聚物，并评估了其抗癌活性、杀伤动力学、降解性和作用机制。方法：探索直链、支链和芳香族疏水侧链单元，如乙基、苄基、丁基、异丁基和己基部分作为调节抗癌活性的共聚单体单元。由于聚合物的疏水性/亲水性平衡决定其抗癌功效，因此改变两种单体之间的进料比以调节其疏水性。结果：值得注意的是，掺入己基部分大大提高了抗癌效率和对癌细胞的杀伤动力学。降解研究表明，聚合物在 4-6 天内完全降解。流式细胞术和乳酸脱氢酶 (LDH) 释放分析表明，含有疏水性共聚单体的共聚物的抗癌机制具有浓度依赖性，IC50 时发生细胞凋亡，2 × IC50 时同时发生细胞凋亡和坏死。相反，不含疏水性共聚单体的均聚物主要通过细胞凋亡机制杀死癌细胞。 结论：聚合物的疏水性在抗癌功效、杀伤动力学和抗癌机制中发挥着重要作用。这项研究为利用聚合物设计新型抗癌剂提供了宝贵的见解。