Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Forckenbeckstraße 50, D-52074 Aachen, Germany; DWI-Leibniz Institute for Interactive Materials e.V., Forckenbeckstraße 50, D-52074 Aachen, Germany.
Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, the Netherlands.
J Colloid Interface Sci. 2019 Mar 22;540:612-622. doi: 10.1016/j.jcis.2019.01.049. Epub 2019 Jan 14.
Facile approaches for the development of new tailored drug carriers are of high importance for the controlled administration of drugs. Herein we report a method for the synthesis of water-soluble reactive copolymers with well-defined architectures for fabrication of redox-sensitive degradable prodrug nanogels for intracellular drug release.
Primary amine-functionalized statistical copolymers were obtained by hydrolysis of poly(N-vinylpyrrolidone-co-N-vinylformamide) copolymers which were synthesized via Reversible Addition-Fragmentation chain-Transfer (RAFT) polymerization. Redox-sensitive degradable nanogels with varying crosslinking densities were synthesized with a redox-sensitive cross-linker. Doxorubicin (DOX) was loaded to form prodrug nanogels (DNG) with hydrodynamic radius from 142 nm to 240 nm.
The nanogels demonstrated slower degradation and retarded drug release rate with increased crosslinking density in the presence of 10 mM reduced glutathione (GSH) at 37 °C. The in vitro release studies revealed that maximum 85% DOX was released in 24 h under a reductive environment. Intracellular drug release profiles in HeLa cells indicated that the DOX delivery rate was tunable via varying crosslinking density of the nanogels. Cell viability assay demonstrated that the blank nanogels were biocompatible in wide concentrations up to 0.5 mg/mL while the DOX-loaded nanogels displayed medium antitumor activity with IC50 (half-maximal inhibitory concentration) of 1.80 μg/mL, 2.57 μg/mL, 3.01 μg/mL for DNG5, DNG10 and DNG15 respectively.
开发新的定制药物载体的简便方法对于药物的控制给药非常重要。在此，我们报告了一种合成具有明确结构的水溶性反应性共聚物的方法，用于制备氧化还原敏感的可降解前药纳米凝胶，以实现细胞内药物释放。
通过水解聚（N-乙烯基吡咯烷酮-co-N-乙烯基甲酰胺）共聚物来获得伯胺官能化的统计共聚物，该共聚物是通过可逆加成-断裂链转移（RAFT）聚合合成的。使用氧化还原敏感的交联剂合成了具有不同交联密度的氧化还原敏感的可降解纳米凝胶。阿霉素（DOX）被加载以形成水动力半径为 142nm 至 240nm 的前药纳米凝胶（DNG）。
在 37°C 下，在 10mM 还原型谷胱甘肽（GSH）存在下，交联密度增加时，纳米凝胶表现出较慢的降解和延迟的药物释放速率。体外释放研究表明，在还原环境下最大 85%的 DOX 在 24 小时内释放。HeLa 细胞内药物释放曲线表明，通过改变纳米凝胶的交联密度可以调节 DOX 的递送速率。细胞活力测定表明，空白纳米凝胶在高达 0.5mg/mL 的宽浓度范围内具有生物相容性，而负载 DOX 的纳米凝胶显示出中等的抗肿瘤活性，DNG5、DNG10 和 DNG15 的 IC50（半最大抑制浓度）分别为 1.80μg/mL、2.57μg/mL 和 3.01μg/mL。
