State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, Gansu, China.
College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Soochow University, Suzhou, 215123, China.
Macromol Rapid Commun. 2018 Mar;39(5). doi: 10.1002/marc.201700744. Epub 2018 Jan 4.
Adaptation of cyclic brush polymer for drug delivery applications remains largely unexplored. Herein, cyclic brush copolymer of poly(2-hydroxyethyl methacrylate-g-poly(N-isopropylacrylamide-st-N-hydroxyethylacrylamide)) (cb-P(HEMA-g-P(NIPAAm-st-HEAAm))), comprising a cyclic core of PHEMA and thermosensitive brushes of statistical copolymer of P(NIPAAm-st-HEAAm), is designed and synthesized successfully via a graft-from approach using atom transfer free radical polymerization from a cyclic multimacroinitiator. The composition of the brush is optimized to endow the resulting cyclic brush copolymer with a lower critical solution temperature (LCST) slightly above the physiological temperature, but lower than the localized temperature of tumor tissue, which is suitable for the hyperthermia-triggered anticancer drug delivery. Critical aggregation concentration determination reveals better stability for the unimolecular nanoparticle formed by the cyclic brush copolymer than that formed by the bottlebrush analogue. The dramatically increased size with elevated temperatures from below to above the LCST confirms hyperthermia-induced aggregation for both formulations. Such structural destabilization promotes significantly the drug release at 40 °C. Most importantly, the drug-loaded cyclic brush copolymer shows enhanced in vitro cytotoxicity against HeLa cells than the bottlebrush counterpart. The better stability and higher therapeutic efficacy demonstrates that the thermosensitive cyclic brush copolymer is a better formulation than bottle brush copolymer for controlled drug release applications.
用于药物输送应用的环刷聚合物的适应性在很大程度上仍未得到探索。在此，通过原子转移自由基聚合从环状多引发剂上进行接枝聚合，成功设计并合成了由聚（2-羟乙基甲基丙烯酸酯- g-聚（N-异丙基丙烯酰胺- st- N-羟乙基丙烯酰胺））（cb-P（HEMA-g-P（NIPAAm-st-HEAAm））组成的环状刷状共聚物，环状核为 PHEMA，温敏刷为 P（NIPAAm-st-HEAAm）的统计共聚物。通过优化刷的组成，使所得环状刷状共聚物具有稍高于生理温度但低于肿瘤组织局部温度的低临界溶液温度（LCST），适用于热疗触发的抗癌药物输送。临界聚集浓度测定表明，与类似的瓶刷相比，由环状刷状共聚物形成的单分子纳米颗粒具有更好的稳定性。从低于 LCST 到高于 LCST 的温度升高导致尺寸急剧增加，证实了两种配方的热诱导聚集。这种结构失稳显著促进了在 40°C 时的药物释放。最重要的是，与瓶刷对应物相比，负载药物的环状刷状共聚物对 HeLa 细胞的体外细胞毒性增强。更好的稳定性和更高的治疗效果表明，热敏性环状刷状共聚物是控制药物释放应用中比瓶刷共聚物更好的制剂。
