Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors  

作　　者：Yang Zhou Fan Tong Weilong Gu Siqin He Xiaotong Yang Jiamei Li Yue-Dong Gao Huile Gao 

机构地区：[1]Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry,Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology,West China School of Pharmacy,Sichuan University,Chengdu 610064,China [2]Core Technology Facility of Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [3]Chinese Academy of Sciences Territorial Core Facility of Kunming Biological Diversity Regional Center,Kunming 650223,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第3期1416-1431,共16页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(81961138009,China);the Key Research and Development Program of Science and Technology Department of Sichuan Province(No.2020YFS0570,China);111 Project(B18035,China);the Fundamental Research Funds for the Central Universities(China);the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China(China)。

摘　　要：Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

关 键 词：Bilirubin nanoparticles ROS-responsive drug release Charge reversal Photodynamic therapy Hypoxia DICLOFENAC LDHA inhibition HIF-1a inhibition 

分 类 号：R943[医药卫生—药剂学]