Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors.
10.1016/j.apsb.2021.12.001
- Author:
Yang ZHOU
1
;
Fan TONG
1
;
Weilong GU
1
;
Siqin HE
1
;
Xiaotong YANG
1
;
Jiamei LI
1
;
Yue-Dong GAO
2
;
Huile GAO
1
Author Information
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.
- Publication Type:Journal Article
- Keywords:
Bilirubin nanoparticles;
Charge reversal;
Diclofenac;
HIF-1α inhibition;
Hypoxia;
LDHA inhibition;
Photodynamic therapy;
ROS-responsive drug release
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1416-1431
- CountryChina
- Language:English
-
Abstract:
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.
