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

Acta Pharmaceutica Sinica B

卷:12

Huile Gao¹  Yue-Dong Gao²  Siqin He³  Jiamei Li³  Xiaotong Yang³  Yang Zhou³  Fan Tong³  Weilong Gu³ 

[1] Chinese Academy of Sciences Territorial Core Facility of Kunming Biological Diversity Regional Center, Kunming 650223, China;

[2] Core Technology Facility of Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;

[3] 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;

关键词: Bilirubin nanoparticles;    ROS-responsive drug release;    Charge reversal;    Photodynamic therapy;    Hypoxia;    Diclofenac;   

DOI  :  

来源: DOAJ

【 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-1α (HIF-1α) 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.

【 授权许可】

Unknown