Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.
Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China.
ACS Biomater Sci Eng. 2020 Apr 13;6(4):2167-2174. doi: 10.1021/acsbiomaterials.0c00125. Epub 2020 Mar 18.
Microenvironments of various solid tumors are characterized by hypoxia. Herein, we report a novel nanoparticle that can selectively release loaded drugs in hypoxic environments. The nanoparticle was prepared using a hypoxia-responsive amphiphilic polymer in aqueous media. The polymer was synthesized by conjugating a hydrophobic small molecule, 4-nitrobenzyl (3-azidopropyl) carbamate, to the side chains of an mPEG-PPLG copolymer. Doxorubicin (DOX) could be loaded into the nanoparticles with a high efficiency of 97.8%. The generated drug-loaded micellar nanoparticles (PPGN@DOX) presented hypoxia-sensitive drug release behavior in vitro. Meanwhile, PPGN@DOX could be effectively internalized by 4T1 cells and could release DOX into the cell nuclei under hypoxic conditions. The in vitro anticancer results suggested that PPGN@DOX presented superior tumor cell-killing ability compared with free DOX in hypoxic environments. Furthermore, PPGN@DOX prolonged the blood circulation time and improved the biological distribution of DOX, resulting in increased antitumor outcomes and reduced side effects in vivo. Overall, the present work demonstrates that hypoxia-responsive nanoparticles have great application potential in the treatment of hypoxic tumors.
各种实体瘤的微环境的特点是缺氧。在此，我们报告了一种新型的纳米粒子，它可以在缺氧环境中选择性地释放所装载的药物。该纳米粒子是在水介质中使用对缺氧反应的两亲聚合物制备的。聚合物通过将疏水分子 4-硝基苄基（3-叠氮丙基）碳酸酯连接到 mPEG-PPLG 共聚物的侧链上而合成。阿霉素（DOX）可以以 97.8％的高效率被负载到纳米粒子中。所生成的载药胶束纳米粒子（PPGN@DOX）在体外表现出缺氧敏感的药物释放行为。同时，PPGN@DOX 可以被 4T1 细胞有效内化，并可以在缺氧条件下将 DOX 释放到细胞核中。体外抗癌结果表明，与缺氧环境中的游离 DOX 相比，PPGN@DOX 表现出优异的肿瘤杀伤能力。此外，PPGN@DOX 延长了 DOX 的血液循环时间，并改善了其生物分布，从而在体内提高了抗肿瘤效果并降低了副作用。总体而言，本工作表明，缺氧反应性纳米粒子在治疗缺氧肿瘤方面具有很大的应用潜力。
