School of Materials Science and Engineering, Tianjin University , Tianjin 300072, P.R. China.
ACS Appl Mater Interfaces. 2013 Dec 26;5(24):13216-26. doi: 10.1021/am404213w. Epub 2013 Dec 13.
Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.
基于一种酸可降解的环苄叉缩醛基（CAB）功能化的聚（2,4,6-三甲氧基苄叉-1,1,1-三（羟甲基）乙烷甲基丙烯酸酯）-g-SS-聚（乙二醇）（PTTMA-g-SS-PEG）接枝共聚物，设计并制备了一种 pH 和还原双重响应性的可分解纳米粒子用于高效载药和改善姜黄素（CUR）的细胞内释放。该共聚物可通过 RAFT 共聚反应和偶联反应轻易合成。在生理 pH 条件下，由 PTTMA-g-SS-PEG 共聚物自组装形成的纳米粒子稳定，而在弱酸和还原环境中会迅速分解，这是由于疏水性 PTTMA 核中的 CAB 水解和二硫键连接的可分离 PEG 壳的断裂。PTTMA-g-SS-PEG 纳米粒子对 CUR 具有优异的载药能力，载药量高达 19.2%，包封率为 96.0%。在体外 20 h 内，在正常生理条件下，负载 CUR 的纳米粒子中只有不到 15.0%的 CUR 释放，而在存在还原剂和类似内涵体/溶酶体和细胞质微环境的弱酸条件下，94.3%的 CUR 释放。共聚焦荧光显微镜显示，与负载 CUR 的还原不响应性 PTTMA-g-PEG NPs 和游离 CUR 相比，负载 CUR 的 PTTMA-g-SS-PEG NPs 能更有效地将 CUR 释放到 EC-109 细胞内。体外细胞毒性研究表明，空白 PTTMA-g-SS-PEG NPs 在高达 1.0 mg/mL 的浓度下表现出低毒性，而负载 CUR 的 PTTMA-g-SS-PEG NPs 对 EC-109 和 HepG-2 细胞的生长抑制作用明显优于还原不响应性对照物和游离 CUR。因此，上述结果表明，pH 和还原双重响应性可分解的 PTTMA-g-SS-PEG NPs 可能成为用于主动载药和促进全身癌症化疗中细胞内药物传递的新型纳米载体。
