An In Vitro-In Vivo Comparative Study Using Highly Sensitive Radioisotopic Assays to Assess the Predictive Power of...

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• Microfluidic BBB-on-a-chip (microBBB) models offer promise for studying central nervous system (CNS) diseases and therapeutics.
• However, their predictive accuracy for drug brain uptake requires further validation with diverse compounds.

Purpose of the Study:

• To evaluate the in vitro-in vivo correlation of drug brain uptake using microfluidic BBB models compared to Transwell models.
• To assess the predictive capacity of microBBB for targeted nanoparticle delivery to the brain.

Main Methods:

• In vivo brain uptake of nine radiolabeled compounds in mice was measured and compared to in vitro data from microfluidic BBB and Transwell models.
• Brain-to-plasma concentration ratios (B/P) were calculated using radioisotopic measurements.
• Uptake of angiopep2-conjugated nanoparticles (ANG2-NP) was assessed in both models.

Main Results:

• The microfluidic BBB model demonstrated a strong in vitro-in vivo correlation (r = 0.8081, R² = 0.6530) for drug brain permeability.
• The Transwell model showed a weaker correlation (r = 0.6467, R² = 0.4182).
• Microfluidic BBB models accurately reflected in vivo nanoparticle uptake, distinguishing targeted from non-targeted delivery, unlike Transwell models.

Conclusions:

• Microfluidic BBB models provide a more predictive platform for assessing drug brain permeability than Transwell models.
• These models show significant potential for advancing CNS drug discovery and development, including targeted delivery systems.