Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells
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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/10/2463 |
| _version_ | 1797572596681670656 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Mar Gil |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T20:58:04Z |
| format | Article |
| id | doaj.art-e603b3eed6d04f5284bf5147d9e90211 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T20:58:04Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e603b3eed6d04f5284bf5147d9e902112023-11-19T17:44:53ZengMDPI AGPharmaceutics1999-49232023-10-011510246310.3390/pharmaceutics15102463Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial CellsMar Gil0Lareen Khouri1Imma Raurell2Diana Rafael3Fernanda Andrade4Ibane Abasolo5Simo Schwartz6María Martínez-Gómez7María Teresa Salcedo8Juan Manuel Pericàs9Diana Hide10Mingxing Wei11Norman Metanis12Joan Genescà13María Martell14Liver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainInstitut of Chemistry, Casali Center for Applied Chemistry, The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, IsraelLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainClinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, SpainClinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, SpainClinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, SpainClinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, 08035 Barcelona, SpainLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainPathology Department, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, SpainLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainCellvax, SAS Villejuif Bio Park, 93230 Villejuif, FranceInstitut of Chemistry, Casali Center for Applied Chemistry, The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, IsraelLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainLiver Disease Group, Liver Unit, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Hospital Campus, Universitat Autonòma de Barcelona (UAB), 08035 Barcelona, SpainIn 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.https://www.mdpi.com/1999-4923/15/10/2463chronic liver diseaseliver fibrosispeptide ligandsportal hypertensiontherapytargeted polymeric micelles |
| spellingShingle | 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 Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells Pharmaceutics chronic liver disease liver fibrosis peptide ligands portal hypertension therapy targeted polymeric micelles |
| title | Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells |
| title_full | Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells |
| title_fullStr | Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells |
| title_full_unstemmed | Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells |
| title_short | Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells |
| title_sort | optimization of statin loaded delivery nanoparticles for treating chronic liver diseases by targeting liver sinusoidal endothelial cells |
| topic | chronic liver disease liver fibrosis peptide ligands portal hypertension therapy targeted polymeric micelles |
| url | https://www.mdpi.com/1999-4923/15/10/2463 |
| work_keys_str_mv | AT margil optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT lareenkhouri optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT immaraurell optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT dianarafael optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT fernandaandrade optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT ibaneabasolo optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT simoschwartz optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT mariamartinezgomez optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT mariateresasalcedo optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT juanmanuelpericas optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT dianahide optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT mingxingwei optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT normanmetanis optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT joangenesca optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells AT mariamartell optimizationofstatinloadeddeliverynanoparticlesfortreatingchronicliverdiseasesbytargetingliversinusoidalendothelialcells |