National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, China.
Colloids Surf B Biointerfaces. 2020 Oct;194:111223. doi: 10.1016/j.colsurfb.2020.111223. Epub 2020 Jun 25.
With the utilization of high concentration reactive oxygen species (ROS) in tumor microenvironment, PEG-doxorubicin (PEG-DOX) prodrug was synthesized via a thioketal moiety as the linker, which was ROS cleavable to trigger DOX release from the self-assembled prodrug nanoparticles. The in vitro ROS sensitivity of prodrug nanoparticles (NPs) was investigated in Fenton agent and HO, and the disassembly of NPs was more sensitive to Fenton reagent. After internalized in HepG2 cells via endocytosis, the cellular ROS consuming test revealed intracellular DOX release. The pharmacokinetics and biodistribution study demonstrated that the in vivo elimination of NPs was significantly improved and the NPs were passively targeted to tumor tissues via EPR effect. The ROS-responsive prodrug NPs exhibited excellent antitumor activity in HepG2 tumor-bearing nude mice, remarkably induced tumor cells apoptosis and reduced the systemic toxicity of DOX. Our study revealed the ROS responsive prodrug nanoparticle is an effective strategy to fabricate nanomedicine for cancer chemotherapy.
利用肿瘤微环境中高浓度的活性氧（ROS），通过硫缩酮作为连接物合成了 PEG-阿霉素（PEG-DOX）前药，该前药可被 ROS 切割，从而从自组装的前药纳米颗粒中触发 DOX 的释放。在 Fenton 试剂和 HO 中研究了前药纳米颗粒（NPs）的体外 ROS 敏感性，并且 NPs 的解组装对 Fenton 试剂更敏感。通过内吞作用被 HepG2 细胞内化后，细胞内 ROS 消耗试验显示细胞内 DOX 的释放。药代动力学和生物分布研究表明，体内 NPs 的消除得到了显著改善，并且 NPs 通过 EPR 效应被动靶向肿瘤组织。ROS 响应性前药纳米颗粒在 HepG2 荷瘤裸鼠中表现出优异的抗肿瘤活性，显著诱导肿瘤细胞凋亡并降低 DOX 的全身毒性。我们的研究揭示了 ROS 响应性前药纳米颗粒是用于癌症化疗的纳米医学的有效策略。
