2. Academic Validation
  3. ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis

ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis

  • J Control Release. 2024 Aug 12:374:112-126. doi: 10.1016/j.jconrel.2024.08.006.
Qigu Yao 1,  Beiduo Wang 2,  Jiong Yu 3,  Qiaoling Pan 4,  Yingduo Yu 1,  Xudong Feng 1,  Wenyi Chen 1,  Jinfeng Yang 4,  Changyou Gao 5,  Hongcui Cao 6
Affiliations

Affiliations

  • 1 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China.
  • 2 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou City 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City 310003, China.
  • 3 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City 310003, China; Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-chemical and Aging-related Injuries, 79 Qingchun Rd, Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou, China.
  • 4 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou, China.
  • 5 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou City 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City 310003, China. Electronic address: cygao@zju.edu.cn.
  • 6 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City 310003, China; Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-chemical and Aging-related Injuries, 79 Qingchun Rd, Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou, China. Electronic address: hccao@zju.edu.cn.
PMID: 39117112 DOI: 10.1016/j.jconrel.2024.08.006
Abstract

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a Reactive Oxygen Species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived Organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced Apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating Apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.

Keywords

Mesenchymal stem cell; Mitochondria; Organoid; Primary sclerosing cholangitis; ROS-responsive nanoparticles.

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