具有核交联和 pH/氧化还原双重响应特性的双靶向纳米粒子，用于增强细胞内药物递送。
Dual-targeting nanoparticles with core-crosslinked and pH/redox-bioresponsive properties for enhanced intracellular drug delivery.
机构信息
State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tianjin Polytechnic University, Tianjin 300387, China.
State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tianjin Polytechnic University, Tianjin 300387, China.
出版信息
J Colloid Interface Sci. 2019 Mar 22;540:66-77. doi: 10.1016/j.jcis.2019.01.021. Epub 2019 Jan 7.
Multifunctional nanoparticles (NPs) with high blood-stability, tumor-targeting ability, and stimuli-bioresponsive drug release behaviors are urgently demanded. Herein, folic acid (FA) and galactose (GAL) functionalized, core-crosslinked NPs (CC NPs) with dual-targeting and pH/redox-bioresponsive properties were developed based on amphiphilic FA-poly(6-O-methacryloyl-d-galactopyranose)-b-poly[2-(diisopropylamino) ethyl methacrylate-co-pyridyl disulfide methylacrylate] [FA-PMAgGP-b-P(DPA-co-PDEMA), termed as FA-PMgDP] block copolymers, and then investigated for facilitated hepatoma-targeting delivery of doxorubicin (DOX). A series of PMgDP copolymers were synthesized though two-step RAFT copolymerization followed by acid-induced acetal deprotection reaction. Their well-defined chemical structures and compositions were characterized by H NMR and gel permeation chromatography. Nano-sized, non-crosslinked PMgDP NPs (PMgDP NC NPs) with sizes of less than 25 nm in aqueous solution were self-assembled via the solvent exchange method, and PMgDP CC NPs were readily prepared in the presence of dithiothreitol. The drug-loading content of PMgDP CC NPs was up to 15.8% and its entrapment efficiency was 89.0%. In normal physiological conditions, 11.6% of DOX was released from DOX-loaded PMgDP CC NPs at 25 h, whereas in analogous intracellular microenvironment, 95.5% was released at 11 h owing to the acid-induced protonation of tertiary amine and reductive cleavage of disulfide bond in the hydrophobic core. In a cellular uptake study, FA and GAL-mediated, active, dual-targeted DOX-loaded FA-PMgDP CC NPs showed a 3.54-fold increase in cellular uptake efficiency to HepG2 cells compared to that of shown by single GAL-targeted, DOX-loaded PMgDP NC NPs. Results of in vitro cytotoxicity study showed that blank FA-PMgDP CC NPs exhibited good biocompatibility, whereas dual-targeting DOX-loaded FA-PMgDP CC NPs increased cell apoptosis. Therefore, the above results indicated that the well-constructed FA-PMgDP CC NPs with multi-synergistic effect may serve as new nanocarriers in the field of precise hepatoma-targeting drug delivery.
多功能纳米粒子（NPs）具有高血液稳定性、肿瘤靶向能力和刺激生物响应性药物释放行为，因此迫切需要开发。在此，基于两亲性叶酸（FA）-聚（6-O-甲酰基-d-半乳糖吡喃糖）-b-聚[2-（二异丙基氨基）乙基甲基丙烯酸酯-co-吡啶二硫代甲基丙烯酸甲酯] [FA-PMAgGP-b-P（DPA-co-PDEMA），称为 FA-PMgDP]嵌段共聚物，开发了具有双重靶向和 pH/氧化还原生物响应性的叶酸（FA）和半乳糖（GAL）功能化的核交联 NPs（CC NPs），然后研究了其促进肝癌靶向递送阿霉素（DOX）的能力。通过两步 RAFT 共聚反应和酸诱导缩醛去保护反应合成了一系列 PMgDP 共聚物。通过 H NMR 和凝胶渗透色谱对其进行了明确的化学结构和组成的表征。通过溶剂交换法自组装纳米尺寸、未交联的 PMgDP NPs（PMgDP NC NPs），尺寸小于 25nm 在水溶液中，在二硫苏糖醇的存在下很容易制备 PMgDP CC NPs。PMgDP CC NPs 的载药量高达 15.8%，包封率为 89.0%。在正常生理条件下，负载 DOX 的 PMgDP CC NPs 在 25h 时释放了 11.6%的 DOX，而在类似的细胞内微环境中，由于疏水性核中叔胺的质子化和二硫键的还原断裂，95.5%的 DOX 在 11h 内释放。在细胞摄取研究中，FA 和 GAL 介导的主动双重靶向 DOX 负载的 FA-PMgDP CC NPs 与仅 GAL 靶向的 DOX 负载的 PMgDP NC NPs 相比，对 HepG2 细胞的细胞摄取效率提高了 3.54 倍。体外细胞毒性研究结果表明，空白 FA-PMgDP CC NPs 表现出良好的生物相容性，而双重靶向 DOX 负载的 FA-PMgDP CC NPs 增加了细胞凋亡。因此，上述结果表明，具有多协同效应的精心构建的 FA-PMgDP CC NPs 可能成为精准肝癌靶向药物递送领域的新型纳米载体。
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