Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells

Mar Gil, Lareen Khouri, Imma Raurell, Diana Rafael, Fernanda Andrade, Ibane Abasolo, Simo Schwartz, María Martínez-Gómez, María Teresa Salcedo, Juan Manuel Pericàs, Diana Hide, Mingxing Wei, Norman Metanis*, Joan Genescà, María Martell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we developed functionalized polymeric micelles (FPMs) loaded with simvastatin (FPM-Sim) as a drug delivery system to target liver sinusoidal endothelial cells (LSECs) for preserving liver function in chronic liver disease (CLD). Polymeric micelles (PMs) were functionalized by coupling peptide ligands of LSEC membrane receptors CD32b, CD36 and ITGB3. Functionalization was confirmed via spectroscopy and electron microscopy. In vitro and in vivo FPM-Sim internalization was assessed by means of flow cytometry in LSECs, hepatocytes, Kupffer and hepatic stellate cells from healthy rats. Maximum tolerated dose assays were performed in healthy mice and efficacy studies of FPM-Sim were carried out in bile duct ligation (BDL) and thioacetamide (TAA) induction rat models of cirrhosis. Functionalization with the three peptide ligands resulted in stable formulations with a greater degree of in vivo internalization in LSECs than non-functionalized PMs. Administration of FPM-Sim in BDL rats reduced toxicity relative to free simvastatin, albeit with a moderate portal-pressure-lowering effect. In a less severe model of TAA-induced cirrhosis, treatment with FPM-CD32b-Sim nanoparticles for two weeks significantly decreased portal pressure, which was associated with a reduction in liver fibrosis, lower collagen expression as well as the stimulation of nitric oxide synthesis. In conclusion, CD32b-FPM stands out as a good nanotransporter for drug delivery, targeting LSECs, key inducers of liver injury.

Original languageAmerican English
Pages (from-to)2463-2460
Number of pages4
JournalPharmaceutics
Volume15
Issue number10
DOIs
StatePublished - 14 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • chronic liver disease
  • liver fibrosis
  • peptide ligands
  • portal hypertension
  • targeted polymeric micelles
  • therapy

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