2. Academic Validation
  3. Remodeling of imbalanced extracellular matrix homeostasis for reversal of pancreatic fibrosis

Remodeling of imbalanced extracellular matrix homeostasis for reversal of pancreatic fibrosis

  • Biomaterials. 2023 Jan;292:121945. doi: 10.1016/j.biomaterials.2022.121945.
Liang Qi 1,  Han Han 2,  Meng-Meng Han 2,  Ying Sun 2,  Lei Xing 3,  Hu-Lin Jiang 4,  Stephen J Pandol 5,  Ling Li 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
  • 2 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.
  • 4 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jianghulin3@gmail.com.
  • 5 Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Basic and Translational Pancreatic Research, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Electronic address: Stephen.Pandol@cshs.org.
  • 6 Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, 210009, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China. Electronic address: lingli@seu.edu.cn.
PMID: 36508773 DOI: 10.1016/j.biomaterials.2022.121945
Abstract

Pancreatic fibrosis is mainly manifested by imbalance in extracellular matrix (ECM) homeostasis due to excessive deposition of collagen in pancreas by activated pancreatic stellate cells (PSCs). Recently, some drugs have exhibited therapeutic potentials for the treatment of pancreatic fibrosis; however, currently, no effective clinical strategy is available to remodel imbalanced ECM homeostasis because of inferior targeting abilities of drugs and collagen barriers that hinder the efficient delivery of drugs. Herein, we design and prepare collagen-binding peptide (CBP) and collagenase I co-decorated dual drug-loaded lipid nanoparticles (named AT-CC) for pancreatic fibrosis therapy. Specifically, AT-CC can target fibrotic pancreas via the CBP and degrade excess collagen by the grafted collagenase I, thereby effectively delivering all-trans-retinoic acid (ATRA) and ammonium tetrathiomolybdate (TM) into pancreas. The released ATRA can reduce collagen overproduction by inhibiting the activation of PSCs. Moreover, the released TM can restrain lysyloxidase activation, consequently reducing collagen cross-linking. The combination of ATRA and TM represses collagen synthesis and reduces collagen cross linkages to restore ECM homeostasis. The results of this research suggest that AT-CC is a safe and efficient collagen-targeted degradation drug-delivery system for reversing pancreatic fibrosis. Furthermore, the strategy proposed herein will offer an innovative platform for the treatment of chronic pancreatitis.

Keywords

Collagen-binding peptide; Collagenase I; Extracellular matrix homeostasis; Pancreatic fibrosis; Pancreatic stellate cell.

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