Limits...
A cell-based computational modeling approach for developing site-directed molecular probes.

Yu JY, Zheng N, Mane G, Min KA, Hinestroza JP, Zhu H, Stringer KA, Rosania GR - PLoS Comput. Biol. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.

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.

Show MeSH

Related in: MedlinePlus

Virtual screening of monobasic compounds based differential tissue distribution in the airways and alveoli.The combinations of logPn and pKa were used as input. For simulations, the initial dose was set to 1 mg/kg for airways and alveoli. Contour lines indicate: A) The calculated AUC (unit: mg/ml*min) in airways; B) The AUC (unit: mg/ml*min) in alveoli; C) The AUC contrast ratio of airways to alveoli; D) The mass percentage (%) in alveoli relative to the total mass in lung; E) The mass percentage (%) in airways relative to the total mass in lung; F) The mass ratio of alveoli to airway. Matlab scripts used to generate plots A–C (Text S1) and D–F (Text S2) are included in the supplementary materials.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3285574&req=5

pcbi-1002378-g002: Virtual screening of monobasic compounds based differential tissue distribution in the airways and alveoli.The combinations of logPn and pKa were used as input. For simulations, the initial dose was set to 1 mg/kg for airways and alveoli. Contour lines indicate: A) The calculated AUC (unit: mg/ml*min) in airways; B) The AUC (unit: mg/ml*min) in alveoli; C) The AUC contrast ratio of airways to alveoli; D) The mass percentage (%) in alveoli relative to the total mass in lung; E) The mass percentage (%) in airways relative to the total mass in lung; F) The mass ratio of alveoli to airway. Matlab scripts used to generate plots A–C (Text S1) and D–F (Text S2) are included in the supplementary materials.

Mentions: For virtual screening experiments, molecules with maximal tissue exposure (AUC) in the airways after inhalation were identified by using combinations of logPn and pKa as input parameters in a multiscale, cell-based lung transport model (Figure 2). For weak bases, lower lipophilicity and higher pKa promoted intracellular retention and led to greater local exposure relative to the alveoli (Figure 2A, B). The calculated airway/alveoli exposure ratio (Figure 2C) ranged from 100 to 700 and increased with lowered logPn (increasing hydrophilicity) and higher pKa (greater positively charged fraction at physiological pH) Essentially, cell-permeant, hydrophilic molecules harboring a fixed positive charge showed the greatest accumulation and retention in the cells of the upper airway relative to the alveoli, following IT administration.


A cell-based computational modeling approach for developing site-directed molecular probes.

Yu JY, Zheng N, Mane G, Min KA, Hinestroza JP, Zhu H, Stringer KA, Rosania GR - PLoS Comput. Biol. (2012)

Virtual screening of monobasic compounds based differential tissue distribution in the airways and alveoli.The combinations of logPn and pKa were used as input. For simulations, the initial dose was set to 1 mg/kg for airways and alveoli. Contour lines indicate: A) The calculated AUC (unit: mg/ml*min) in airways; B) The AUC (unit: mg/ml*min) in alveoli; C) The AUC contrast ratio of airways to alveoli; D) The mass percentage (%) in alveoli relative to the total mass in lung; E) The mass percentage (%) in airways relative to the total mass in lung; F) The mass ratio of alveoli to airway. Matlab scripts used to generate plots A–C (Text S1) and D–F (Text S2) are included in the supplementary materials.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285574&req=5

pcbi-1002378-g002: Virtual screening of monobasic compounds based differential tissue distribution in the airways and alveoli.The combinations of logPn and pKa were used as input. For simulations, the initial dose was set to 1 mg/kg for airways and alveoli. Contour lines indicate: A) The calculated AUC (unit: mg/ml*min) in airways; B) The AUC (unit: mg/ml*min) in alveoli; C) The AUC contrast ratio of airways to alveoli; D) The mass percentage (%) in alveoli relative to the total mass in lung; E) The mass percentage (%) in airways relative to the total mass in lung; F) The mass ratio of alveoli to airway. Matlab scripts used to generate plots A–C (Text S1) and D–F (Text S2) are included in the supplementary materials.
Mentions: For virtual screening experiments, molecules with maximal tissue exposure (AUC) in the airways after inhalation were identified by using combinations of logPn and pKa as input parameters in a multiscale, cell-based lung transport model (Figure 2). For weak bases, lower lipophilicity and higher pKa promoted intracellular retention and led to greater local exposure relative to the alveoli (Figure 2A, B). The calculated airway/alveoli exposure ratio (Figure 2C) ranged from 100 to 700 and increased with lowered logPn (increasing hydrophilicity) and higher pKa (greater positively charged fraction at physiological pH) Essentially, cell-permeant, hydrophilic molecules harboring a fixed positive charge showed the greatest accumulation and retention in the cells of the upper airway relative to the alveoli, following IT administration.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.

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.

Show MeSH
Related in: MedlinePlus