2. Academic Validation
  3. Ursodeoxycholic acid loaded dual-modified graphene oxide nanocomposite alleviates cholestatic liver injury through inhibiting hepatocyte apoptosis

Ursodeoxycholic acid loaded dual-modified graphene oxide nanocomposite alleviates cholestatic liver injury through inhibiting hepatocyte apoptosis

  • Colloids Surf B Biointerfaces. 2024 Jun:238:113904. doi: 10.1016/j.colsurfb.2024.113904.
Wanyi Zhou 1,  Xinrui Yang 2,  Yaru Yin 2,  Si Chen 3,  Luxun Yang 2,  Tao Li 2,  Jing Liu 2,  Binghui Lu 2,  Zhangyou Yang 4,  Rong Li 5,  Mingman Zhang 6
Affiliations

Affiliations

  • 1 Department of Urology, Institute of Surgery Research, Army Medical Center, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 2 State Key Laboratory of Trauma and Chemical Poisoning, Military Key Laboratory of Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China.
  • 3 Department of Pediatric Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400015, China.
  • 4 Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 5 State Key Laboratory of Trauma and Chemical Poisoning, Military Key Laboratory of Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lrong361@126.com.
  • 6 Department of Pediatric Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400015, China. Electronic address: zhangmingman_a@163.com.
PMID: 38603845 DOI: 10.1016/j.colsurfb.2024.113904
Abstract

Ursodeoxycholic acid (UDCA) is the preferred treatment for various types of cholestasis, however, its effectiveness is limited because of its insolubility in water. We used polyethylene glycol (PEG) and cationic polymer polyethylenimine (PEI) to double-modify graphite oxide (PPG) as a drug delivery system. UDCA was successfully loaded onto PPG through intermolecular interactions to form UDCA-PPG nanoparticles. UDCA-PPG nanoparticles not only improve the solubility and dispersibility of UDCA, but also have good biocompatibility and stability, which significantly improve the delivery rate of UDCA. The results indicated that UDCA-PPG significantly reduced ROS levels, promoted cell proliferation, protected mitochondrial membrane potential, reduced DNA damage and reduced Apoptosis in the DCA-induced cell model. In a mouse cholestasis model established by bile duct ligation (BDL), UDCA-PPG improved liver necrosis, fibrosis, and mitochondrial damage and reduced serum ALT and AST levels, which were superior to those in the UDCA-treated group. UDCA-PPG reduced the expression of the apoptosis-related proteins, Caspase-3 and Bax, increased the expression of Bcl-2, and reduced the expression of the oxidative stress-related proteins, NQO and HO-1, as well as the autophagy-related proteins LC3, p62 and p-p62. Therefore, UDCA-PPG can enhance the therapeutic effect of UDCA in cholestasis, by significantly improving drug dispersibility and stability, extending circulation time in vivo, promoting absorption, decreasing ROS levels, enhancing Autophagy flow and inhibiting Apoptosis via the Bcl-2/Bax signaling pathway.

Keywords

Apoptosis; Autophagy; Cholestatic liver injury; Graphene oxide; Ursodeoxycholic acid.

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