Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery.
Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery.
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DOI：
10.1002/marc.201700744
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发表时间：
2018-03
影响因子：
4.6
通讯作者：
Xiaoyan Tu;Chao Meng;Yunfei Wang;Liwei Ma;Baoyan Wang;Jinlin He;P. Ni;Xiangling Ji;Ming-Zhu Liu;Hua Wei
中科院分区：
文献类型：
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作者：
Xiaoyan Tu;Chao Meng;Yunfei Wang;Liwei Ma;Baoyan Wang;Jinlin He;P. Ni;Xiangling Ji;Ming-Zhu Liu;Hua Wei
用于药物递送应用的环状刷状聚合物的适应性仍然在很大程度上未被探索。本文采用原子转移自由基聚合法，以环状多大分子引发剂为引发剂，设计并合成了含有PHEMA环核和P（NIPAAm-st-HEAAm）统计共聚物温敏刷的环状聚（甲基丙烯酸2-羟乙酯-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）。优化刷的组成以赋予所得环状刷共聚物略高于生理温度但低于肿瘤组织的局部温度的较低临界溶解温度（LCST），这适用于高血压触发的抗癌药物递送。临界聚集浓度的测定表明，由环状刷共聚物形成的单分子纳米颗粒比由瓶刷类似物形成的单分子纳米颗粒具有更好的稳定性。随着温度从低于LCST到高于LCST升高，尺寸急剧增加，证实了两种制剂的高血压诱导的聚集。这种结构不稳定显著促进了40 °C下的药物释放。最重要的是，载药的环状刷共聚物显示出比瓶刷对应物增强的对HeLa细胞的体外细胞毒性。更好的稳定性和更高的治疗功效表明，对于药物控制释放应用，热敏环状刷状共聚物是比瓶刷状共聚物更好的制剂。
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.