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Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies
Cosmin Butnarasu1, Giulia Caron1, Daniela Peneda Pacheco2,3
1Department of Molecular Biotechnology and Health Science, University of Torino, Via Quarello15, Torino 10135, Italy.
Abstract:
Mucus represents a strong barrier to tackle for oral or pulmonary administered drugs, especially in mucus-related disorders. This study uses a pathological cystic fibrosis (CF) mucus model to investigate how mucus impacts the passive diffusion of 45 ad hoc commercial drugs selected to maximize physicochemical variability. An in vitro mucosal surface was recreated by coupling the mucus model to a 96-well permeable support precoated with structured layers of phospholipids (parallel artificial membrane permeability assay, PAMPA). Results show that the mucus model was not a mere physical barrier but it behaves like an interactive filter. In nearly one-half of the investigated compounds, the diffusion was reduced by mucus, while other drugs were not sensitive to the mucus barriers. We also found that permeability can be enhanced when drug-calcium salts are formed. This was confirmed with cystic fibrosis sputum as a rough ex vivo model of CF mucus. Since the drug discovery process is characterized by a high rate of failure, the mucus platform is expected to provide an efficient support to early reduce the number of poor-performing drug candidates.
Insights
This study reveals mucus acts as an interactive filter, impacting drug diffusion. Forming drug-calcium salts can enhance permeability, aiding drug discovery for mucus-related disorders.
Area of Science:
- Pharmacology
- Biophysics
- Drug Delivery
Background:
- Mucus presents a significant challenge for oral and pulmonary drug delivery, particularly in mucus-related disorders.
- Understanding drug diffusion through mucus is crucial for developing effective therapeutics.
Purpose of the Study:
- To investigate the impact of mucus on the passive diffusion of various commercial drugs.
- To evaluate a novel in vitro mucus model for drug permeability assessment.
- To identify strategies for enhancing drug permeability through mucus barriers.
Main Methods:
- Development of an in vitro mucus model using cystic fibrosis (CF) mucus.
- Coupling the mucus model with a parallel artificial membrane permeability assay (PAMPA).
- Testing the passive diffusion of 45 commercial drugs with diverse physicochemical properties.
Main Results:
- The mucus model demonstrated an interactive filtering effect, not just a physical barrier.
- Mucus reduced the diffusion of approximately half of the tested drug compounds.
- Drug permeability was enhanced when drugs were formulated as calcium salts, confirmed with ex vivo CF sputum.
Conclusions:
- The developed mucus platform serves as an efficient in vitro tool for early assessment of drug candidates.
- Identifying drugs sensitive to mucus barriers can help reduce late-stage failures in drug discovery.
- Formulating drugs as calcium salts is a potential strategy to overcome mucus-related delivery challenges.
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