Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China.
Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China.
Colloids Surf B Biointerfaces. 2021 May;201:111632. doi: 10.1016/j.colsurfb.2021.111632. Epub 2021 Feb 19.
Prodrug nanoparticles with cleavable moieties sensitive to intracellular stimuli have drawn great attention on cancer chemotherapy. Herein, a reactive oxygen species (ROS)-responsive doxorubicin prodrug mPEG-Phe-TK-Phe-hyd-DOX was synthesized, in which hydrophilic methoxy poly(ethylene glycol) (mPEG) and hydrophobic anticancer drug doxorubicin (DOX) were conjugated with hydrazone (hyd) and ROS-responsive thioketal (TK) moieties. The ROS-responsiveness of prodrug was confirmed by proton nuclear magnetic resonance (H NMR) and dynamic light scattering (DLS). Unexpectedly, the results of in vitro drug release indicated that the hydrazone bond of prodrug nanoparticles was insensitive to pH, which may be due to the strong hydrophobicity, π-π interactions and cation-π interactions jointly inhibited the hydrolysis of hydrazone bonds under acidic conditions. The cellular uptake and in vitro anticancer study showed that ROS-responsive prodrug nanoparticles exhibited faster cellular uptake and better anticancer efficacy. The in vivo experiments showed that the ROS-responsive prodrug nanoparticles had comparable antitumor efficacy with free anticancer drug DOX and reduced organ toxicity. Our results provide novel idea of successfully design multi-stimuli-responsive nano-drug carrier.
具有可裂解部分的前药纳米粒子对细胞内刺激敏感，在癌症化疗方面引起了极大关注。本文合成了一种活性氧（ROS）响应的阿霉素前药 mPEG-Phe-TK-Phe-hyd-DOX，其中亲水性甲氧基聚乙二醇（mPEG）和疏水性抗癌药物阿霉素（DOX）分别与腙（hyd）和 ROS 响应的硫代缩酮（TK）部分连接。通过质子核磁共振（1H NMR）和动态光散射（DLS）证实了前药的 ROS 响应性。出乎意料的是，体外药物释放结果表明前药纳米粒子中的腙键对 pH 不敏感，这可能是由于强疏水性、π-π 相互作用和阳离子-π 相互作用共同抑制了腙键在酸性条件下的水解。细胞摄取和体外抗癌研究表明，ROS 响应性前药纳米粒子具有更快的细胞摄取和更好的抗癌效果。体内实验表明，ROS 响应性前药纳米粒子具有与游离抗癌药物 DOX 相当的抗肿瘤疗效，并降低了器官毒性。我们的研究结果为成功设计多刺激响应性纳米药物载体提供了新的思路。
