化学
活性氧
结合
体内
癌细胞
多重耐药
内吞作用
肿瘤微环境
药理学
药物输送
癌症研究
癌症
生物化学
生物
肿瘤细胞
受体
数学分析
遗传学
数学
生物技术
有机化学
抗生素
作者
Tingting Sun,Jie Xu,Tianbao Chen,Chunlai Tu,Lijuan Zhu,Deyue Yan
出处
期刊:Biomaterials Science
[The Royal Society of Chemistry]
日期:2022-01-01
卷期号:10 (4): 997-1007
被引量:16
摘要
P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug-inhibitor (TPGS-TAM) co-delivery system. Due to its amphiphilic property, the TPGS-TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS-TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.
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