Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis

Jessica Hung,1 Rohni Awasthi,1 Alexander L Klibanov,2– 5 Kimberly A Kelly2 1Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, Virginia, 22908, USA; 2Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville,...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hung J, Awasthi R, Klibanov AL, Kelly KA
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	phage display next-generation sequencing peptide ligands targeted liposomes drug delivery Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/f9ab15a4c71d464981a5324f6f917324
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f9ab15a4c71d464981a5324f6f917324
record_format	dspace
spelling	oai:doaj.org-article:f9ab15a4c71d464981a5324f6f9173242021-12-02T18:45:36ZIdentification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis1178-2013https://doaj.org/article/f9ab15a4c71d464981a5324f6f9173242021-08-01T00:00:00Zhttps://www.dovepress.com/identification-of-novel-ligands-for-targeted-antifibrotic-therapy-of-c-peer-reviewed-fulltext-article-IJNhttps://doaj.org/toc/1178-2013Jessica Hung,1 Rohni Awasthi,1 Alexander L Klibanov,2– 5 Kimberly A Kelly2 1Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, Virginia, 22908, USA; 2Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA; 3Division of Cardiovascular Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA; 4Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, 22908, USA; 5Department of Radiology, University of Virginia, Charlottesville, Virginia, 22908, USACorrespondence: Kimberly A KellyDepartment of Biomedical Engineering, School of Medicine, University of Virginia, Box 800759, Charlottesville, Virginia, 22908, USATel +1 434-243-9352Fax +1 434-982-3870Email kak3x@virginia.eduPurpose: Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas that leads to impaired pancreatic function. The limited therapeutic options and the lack of molecular targeting ligands or non-serum-based biomarkers hinder the development of target-specific drugs. Thus, there is a need for an unbiased, comprehensive discovery and evaluation of pancreatitis-specific ligands.Methods: This study utilized a computational-guided in vivo phage display approach to select peptide ligands selective for cellular components in the caerulein-induced mouse model of CP. The identified peptides were conjugated to pegylated DOPC liposomes via the reverse-phase evaporation method, and the in vivo specificity and pharmacokinetics were determined. As proof of concept, CP-targeted liposomes were used to deliver an antifibrotic small molecular drug, apigenin. Antifibrotic effects determined by pancreatic histology, fibronectin expression, and collagen deposition were evaluated.Results: We have identified five peptides specific for chronic pancreatitis and demonstrated selectivity to activated pancreatic stellate cells, acinar cells, macrophages, and extracellular matrix, respectively. MDLSLKP-conjugated liposomes demonstrated an increased particle accumulation by 1.3-fold in the inflamed pancreas compared to the control liposomes. We also observed that targeted delivery of apigenin resulted in improved acini preservation, a 37.2% and 33.1% respective reduction in collagen and fibronectin expression compared to mice receiving the free drug, and reduced oxidative stress in the liver.Conclusion: In summary, we have developed a systematic approach to profile peptide ligands selective for cellular components of complex disease models and demonstrated the biomedical applications of the identified peptides to improve tissue remodeling in the inflamed pancreas.Keywords: phage display, next-generation sequencing, peptide ligands, targeted liposomes, drug deliveryHung JAwasthi RKlibanov ALKelly KADove Medical Pressarticlephage displaynext-generation sequencingpeptide ligandstargeted liposomesdrug deliveryMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 5495-5512 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	phage display next-generation sequencing peptide ligands targeted liposomes drug delivery Medicine (General) R5-920
spellingShingle	phage display next-generation sequencing peptide ligands targeted liposomes drug delivery Medicine (General) R5-920 Hung J Awasthi R Klibanov AL Kelly KA Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
description	Jessica Hung,1 Rohni Awasthi,1 Alexander L Klibanov,2– 5 Kimberly A Kelly2 1Department of Biomedical Engineering, School of Engineering, University of Virginia, Charlottesville, Virginia, 22908, USA; 2Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA; 3Division of Cardiovascular Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA; 4Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, 22908, USA; 5Department of Radiology, University of Virginia, Charlottesville, Virginia, 22908, USACorrespondence: Kimberly A KellyDepartment of Biomedical Engineering, School of Medicine, University of Virginia, Box 800759, Charlottesville, Virginia, 22908, USATel +1 434-243-9352Fax +1 434-982-3870Email kak3x@virginia.eduPurpose: Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas that leads to impaired pancreatic function. The limited therapeutic options and the lack of molecular targeting ligands or non-serum-based biomarkers hinder the development of target-specific drugs. Thus, there is a need for an unbiased, comprehensive discovery and evaluation of pancreatitis-specific ligands.Methods: This study utilized a computational-guided in vivo phage display approach to select peptide ligands selective for cellular components in the caerulein-induced mouse model of CP. The identified peptides were conjugated to pegylated DOPC liposomes via the reverse-phase evaporation method, and the in vivo specificity and pharmacokinetics were determined. As proof of concept, CP-targeted liposomes were used to deliver an antifibrotic small molecular drug, apigenin. Antifibrotic effects determined by pancreatic histology, fibronectin expression, and collagen deposition were evaluated.Results: We have identified five peptides specific for chronic pancreatitis and demonstrated selectivity to activated pancreatic stellate cells, acinar cells, macrophages, and extracellular matrix, respectively. MDLSLKP-conjugated liposomes demonstrated an increased particle accumulation by 1.3-fold in the inflamed pancreas compared to the control liposomes. We also observed that targeted delivery of apigenin resulted in improved acini preservation, a 37.2% and 33.1% respective reduction in collagen and fibronectin expression compared to mice receiving the free drug, and reduced oxidative stress in the liver.Conclusion: In summary, we have developed a systematic approach to profile peptide ligands selective for cellular components of complex disease models and demonstrated the biomedical applications of the identified peptides to improve tissue remodeling in the inflamed pancreas.Keywords: phage display, next-generation sequencing, peptide ligands, targeted liposomes, drug delivery
format	article
author	Hung J Awasthi R Klibanov AL Kelly KA
author_facet	Hung J Awasthi R Klibanov AL Kelly KA
author_sort	Hung J
title	Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
title_short	Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
title_full	Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
title_fullStr	Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
title_full_unstemmed	Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis
title_sort	identification of novel ligands for targeted antifibrotic therapy of chronic pancreatitis
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/f9ab15a4c71d464981a5324f6f917324
work_keys_str_mv	AT hungj identificationofnovelligandsfortargetedantifibrotictherapyofchronicpancreatitis AT awasthir identificationofnovelligandsfortargetedantifibrotictherapyofchronicpancreatitis AT klibanoval identificationofnovelligandsfortargetedantifibrotictherapyofchronicpancreatitis AT kellyka identificationofnovelligandsfortargetedantifibrotictherapyofchronicpancreatitis
_version_	1718377717321170944

Identification of Novel Ligands for Targeted Antifibrotic Therapy of Chronic Pancreatitis

Ejemplares similares