Synthesis of Thermosensitive Conjugated Triblock Copolymers by Sequential Click Couplings for Drug Delivery and Cell Imaging
Synthesis of Thermosensitive Conjugated Triblock Copolymers by Sequential Click Couplings for Drug Delivery and Cell Imaging
复制标题
DOI：
10.1021/acsbiomaterials.9b00664
复制
发表时间：
2019-07-01
影响因子：
5.8
通讯作者：
Wei, Hua
中科院分区：
文献类型：
--
作者：
Deng, Kaicheng;Zhao, Xuezhi;Wei, Hua
优秀的发光部分和生物相关信号响应部分的优雅集成可以产生先进的聚合物传递系统，同时具有良好的癌症治疗诊断和治疗功能。尽管基于荧光聚芴（PF）或热响应性聚（n -异丙基丙烯酰胺）（PNIPAAm）的聚合物递送系统已经得到了广泛的开发，但由于难以整合不同的合成策略，制备由PF嵌段、PNIPAAm序列和亲水部分组成的三元聚合物配方仍然很少被探索。为此，我们设计并控制合成了一种基于PF和PNIPAAm的两亲性三嵌段共聚物PF11-b-PNIPAAm（120)-b-聚低聚（乙二醇）甲基丙烯酸单甲基醚）（17）(PF11-b-PNIPAAm(120)-b-POEGMA(17))，该共聚物通过suzuki偶联生成的PF和原子转移自由基聚合（ATRP）生成的PNIPAAm和POEGMA之间的顺序点击偶联策略具有明确的结构。所制备的三嵌段共聚物可以自组装成具有核-壳-电晕（CSC）结构的胶束，该胶束由PF部分的内部疏水核组成，用于荧光跟踪和药物封装，PNIPAAm块的热敏中间壳用于热调节药物装载和释放，POEGMA段的亲水外壳用于胶束稳定。有趣的是，在25℃下制备的负载阿霉素（DOX）的胶束比在37℃下制备的类似物具有更大的载药能力，因为前者配方的稳定性更好，从而导致其在HeLa细胞中的体外细胞毒性更高。结合局部高温触发的药物释放谱和通过监测PF部分的荧光有效地在细胞内运输纳米载体，该配方显示了癌症治疗的巨大潜力。
The elegant integration of an excellent light-emitting segment and a biorelevant signal-responsive moiety could generate advanced polymeric delivery systems with simultaneously favorable diagnostic and therapeutic functions with respect to cancer theranostics. Although polymeric delivery systems based on fluorescent polyfluorene (PF) or thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) have been extensively developed, the preparation of a ternary polymer formulation composed of a PF block, a PNIPAAm sequence, and a hydrophilic moiety remains rarely explored likely because of the difficulty in integrating different synthesis strategies for polymer synthesis. To this end, herein we reported the design and controlled synthesis of a PF- and PNIPAAm-based amphiphilic triblock copolymer, PF11-b-PNIPAAm(120)-b-poly(oligo (ethylene glycol) monomethyl ether methacrylate)(17) (PF11-b-PNIPAAm(120)-b-POEGMA(17)), with a well-defined structure by a strategy of sequential click couplings between Suzuki-coupling-generated PF and atom-transfer radical polymerization (ATRP)-produced PNIPAAm and POEGMA. The as-prepared triblock copolymers can self-assemble into micelles with a core-shell-corona (CSC) structure that is composed of an inner hydrophobic core of the PF moiety for fluorescent tracking and drug encapsulation, a thermosensitive middle shell of PNIPAAm block for thermomodulated drug loading and release, and a hydrophilic outer corona of the POEGMA segment for micelle stabilization. Interestingly, the doxorubicin (DOX)-loaded micelles prepared at 25 degrees C had a greater drug loading capacity than the analogues fabricated at 37 degrees C due to the better stability of the former formulation, leading to its higher in vitro cytotoxicity in HeLa cells. Together with the integration of a localized hyperthermia-triggered drug release profile and efficiently intracellular trafficking of the nanocarriers by monitoring the fluorescence of the PF moiety, this formulation demonstrates a great potential for cancer theranostics.