Institute of Bioengineering and Bioimaging, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.
Theranostics. 2021 Aug 21;11(18):8977-8992. doi: 10.7150/thno.60711. eCollection 2021.
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) organocatalytic ring-opening polymerization (OROP) of functional cyclic carbonate monomers, and evaluated for anticancer activity, killing kinetics, degradability and functional mechanism. 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. 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 IC, and both apoptosis and necrosis at 2 × IC. In contrast, the homopolymer without a hydrophobic comonomer killed cancer cells predominantly apoptotic mechanism. 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.
传统抗癌化疗药物的应用受到多药耐药（MDR）发展和转移的多因素性质的阻碍。最近，阳离子聚碳酸酯被报道为新型非常规抗癌剂，可减轻 MDR 并抑制转移。本研究旨在探讨结构-抗癌活性关系。具体而言，使用窄分散性（Ð = 1.12-1.27）的有机催化开环聚合（OROP）合成了一系列具有不同疏水性的阳离子胍基随机共聚物功能性环状碳酸酯单体，并对其抗癌活性、杀伤动力学、可降解性和功能机制进行了评估。线性、支化和芳香疏水性侧链单元，如乙基、苄基、丁基、异丁基和己基作为共聚单体单元，用于调节抗癌活性。由于聚合物的疏水性/亲水性平衡决定了其抗癌功效，因此通过改变两种单体的进料比来调节其疏水性。值得注意的是，引入己基基团大大提高了对癌细胞的抗癌效率和杀伤动力学。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，含有疏水性共单体的共聚物的抗癌机制是浓度依赖性的，在 IC 时为凋亡，在 2×IC 时为凋亡和坏死。相比之下，不含疏水性共单体的均聚物主要通过凋亡机制杀死癌细胞。聚合物的疏水性对抗癌功效、杀伤动力学和抗癌机制起着重要作用。本研究为利用聚合物设计新型抗癌剂提供了有价值的见解。
