State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
Biomaterials. 2012 Sep;33(27):6570-9. doi: 10.1016/j.biomaterials.2012.05.062. Epub 2012 Jun 15.
A new type of redox/pH dual stimuli-responsive poly(methacrylic acid) (PMAA)-based nanohydrogels was prepared from methacrylic acid and N,N-bis(acryloyl)cystamine crosslinker via distillation-precipitation polymerization. The nanohydrogels could be easily degraded into individual linear short chains (M(n) ≈ 1200, M(w)/M(n) < 1.1) in the presence of 10 mM dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX) as a model anti-cancer drug was high efficiently loaded into the nanohydrogels (up to 42.3 wt%) due to the strong electrostatic interactions between the amine group in doxorubicin (DOX) and the carboxyl groups in the nanohydrogels at a physiological pH. The cumulative release profile of the DOX-loaded nanohydrogels showed a low level of drug release (less than 15 wt% in 24 h) at pH 7.4, and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt% in 5 h), exhibiting an obvious pH/redox dual-responsive controlled drug release capability. The drug release behavior of the DOX-loaded nanohydrogels in the presence of GSH was very different from the DTT as the loaded DOX could be quickly released in the presence of GSH, but not in DTT. The possible reason is the synergic effect of reduction and charge exchange of GSH at a low pH. The dose-dependent cytotoxicity of the DOX-loaded nanohydrogels was studied by the CCK-8 assay; the DOX-loaded nanohydrogels could be taken up quickly by human glioma (U251MG cells) via endocytosis, and then biodegraded to release the loaded drugs, which exhibited a comparably anti-tumor efficacy. These nanohydrogels possess many favorable traits, such as excellent biocompatibility and biodegradability, adequate drug loading capacity, minimal drug release under an extracellular condition (non-reductive), and rapid drug release in response to the intracellular level of pH and reducing potential, which endow them as a promise candidate for delivering anti-cancer drugs.
一种新型的氧化还原/ pH 双重刺激响应聚（甲基丙烯酸）（PMAA）基纳米水凝胶是通过蒸馏沉淀聚合由甲 基丙烯酸和 N,N-双（丙烯酰）半胱胺交联剂制备的。在存在 10 mM 二硫苏糖醇（DTT）或谷胱甘肽（GSH）的情况下，纳米水凝胶可以很容易地降解成单个线性短链（M(n) ≈ 1200，M(w)/M(n) < 1.1）。由于阿霉素（DOX）中的氨基与纳米水凝胶中的羧基之间的强静电相互作用，阿霉素（DOX）作为一种模型抗癌药物被高效地负载到纳米水凝胶中（高达 42.3 wt%）在生理 pH 值下。载药纳米水凝胶的累积释放曲线显示在 pH 7.4 时药物释放水平较低（24 小时内低于 15 wt%），在较低 pH（5.0）和还原环境下（5 小时内超过 91 wt%）显著加速，表现出明显的 pH/氧化还原双重响应控制药物释放能力。在 GSH 存在下，载药纳米水凝胶的药物释放行为与 DTT 非常不同，因为负载的 DOX 可以在 GSH 存在下迅速释放，但在 DTT 中不能。可能的原因是在低 pH 下 GSH 的还原和电荷交换的协同作用。通过 CCK-8 测定研究了载药纳米水凝胶的剂量依赖性细胞毒性；载药纳米水凝胶可以通过内吞作用被人神经胶质瘤（U251MG 细胞）快速摄取，然后生物降解以释放负载的药物，表现出相当的抗肿瘤功效。这些纳米水凝胶具有许多优良的特性，如良好的生物相容性和生物降解性、足够的药物负载能力、在细胞外条件下（非还原）药物释放最小以及对细胞内 pH 值和还原电位的快速响应释放，使它们成为递送抗癌药物的有希望的候选物。
