title: A cell-based computational modeling approach for developing site-directed molecular probes.
abstract: Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in vitro cell based assays and in vivo biodistribution studies. To target small molecule probes to the epithelial cells of the upper airways, a multiscale computational model of the lung was first used as a screening tool, in silico. Following virtual screening, cell monolayers differentiated on microfabricated pore arrays and multilayer cultures of primary human bronchial epithelial cells differentiated in an air-liquid interface were used to test the local absorption and intracellular retention patterns of selected probes, in vitro. Lastly, experiments involving visualization of bioimaging probe distribution in the lungs after local and systemic administration were used to test the relevance of computational models and cell-based assays, in vivo. The results of in vivo experiments were consistent with the results of in silico simulations, indicating that mitochondrial accumulation of membrane permeant, hydrophilic cations can be used to maximize local exposure and retention, specifically in the upper airways after intratracheal administration.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Yu
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Gerta
authors.initials: G
authors.lastname: Mane
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Min
authors.forename: Juan P
authors.initials: JP
authors.lastname: Hinestroza
authors.forename: Huaning
authors.initials: H
authors.lastname: Zhu
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stringer
authors.forename: Gus R
authors.initials: GR
authors.lastname: Rosania
mesh_terms: D000042:Absorption; D000818:Animals; D001692:Biological Transport; D001980:Bronchi / Q000166:cytology; D002412:Cations; D002454:Cell Differentiation; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004847:Epithelial Cells / Q000166:cytology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D015335:Molecular Probes / Q000494:pharmacology*; D012984:Software; D014132:Trachea / Q000473:pathology
chemical_list: D002412:Cations; D005456:Fluorescent Dyes; D015335:Molecular Probes