Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery

Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs a...

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Bibliographic Details
Published in:	Journal of controlled release Vol. 322; pp. 457 - 469
Main Authors:	Leal, Jasmim, Peng, Xiujuan, Liu, Xinquan, Arasappan, Dhivya, Wylie, Dennis C., Schwartz, Sarah H., Fullmer, Jason J., McWilliams, Bennie C., Smyth, Hugh D.C., Ghosh, Debadyuti
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 10-06-2020
Subjects:	Bioinformatics Cystic fibrosis Drug delivery Mucosal barriers Mucus Next-generation sequencing Peptides Phage display Phage display Next-generation sequencing Peptides Mucosal barriers Cystic fibrosis Drug delivery Mucus Bioinformatics
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Summary:	Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs and particles from penetrating the mucus barrier. To address this problem, we used combinatorial peptide-presenting phage libraries and next-generation sequencing (NGS) to identify hydrophilic, net-neutral charged peptide coatings that enable penetration through human CF mucus ex vivo with ~600-fold better penetration than control, improve uptake into lung epithelial cells compared to uncoated or PEGylated-nanoparticles, and exhibit enhanced uniform distribution and retention in the mouse lung airways. These peptide coatings address multiple delivery barriers and effectively serve as excellent alternatives to standard PEG surface chemistries to achieve mucus penetration and address some of the challenges encountered using these chemistries. This biomolecule-based strategy can address multiple delivery barriers and hold promise to advance efficacy of therapeutics for diseases like CF. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization and Design: JL, HDCS, and DG; Investigation and Validation: JL, XP, and XL Methodology: JL, HDCS, and DG; Software: JL, DA, and DW; Resources: SHS, JJF and BCM Visualization: JL; Data Curation: JL; Formal Analysis: JL, HDCS, and DG; Writing - Original Draft and Review & Editing: JL, HDCS, and DG; Supervision: HDCS and DG; Funding Acquisition: DG and HDCS JL, HDCS, and DG designed experiments. JL performed experiments. XP and XL assisted in performing experiments. DA and DW collaborated with the development of bioinformatics pipelines and assisted with analysis of the deep sequencing data. SHS, JJF and BCM collected patient samples and managed clinical data. JL, HDCS, and DG analyzed the experiments. JL, HDCS, and DG wrote the manuscript. Author contributions
ISSN:	0168-3659 1873-4995
DOI:	10.1016/j.jconrel.2020.03.032