Non-Invasive, Targeted Nanoparticle-Mediated Drug Delivery across a Novel Human BBB Model.

Area of Science:

• Neuroscience
• Biotechnology
• Materials Science

Background:

• The blood-brain barrier (BBB) restricts the entry of therapeutics into the central nervous system (CNS).
• Developing effective drug delivery systems for neurological disorders is challenging due to the BBB.
• Poly(lactic-co-glycolic acid) (PLGA) nanoparticles offer potential for encapsulating and delivering therapeutic compounds.

Purpose of the Study:

• To encapsulate a model hydrophilic compound (FITC-dextran) into PLGA nanoparticles.
• To functionalize PLGA nanoparticles with a peptide ligand (DAS) targeting alpha 7 nicotinic receptors on brain endothelial cells.
• To evaluate the efficacy of DAS-conjugated nanoparticles in crossing the BBB using an in vitro model.

Main Methods:

• Encapsulation of FITC-dextran (70 kDa) into PLGA nanoparticles, achieving over 60% encapsulation efficiency.
• Chemical modification of nanoparticle surface with DAS peptide for receptor-mediated transcytosis (RMT) across the BBB.
• Utilizing a triculture in vitro BBB model that mimics in vivo conditions (TEER ≥230, ZO1 expression).

Main Results:

• DAS-conjugated nanoparticles successfully transported FITC-dextran across the in vitro BBB model.
• A fourteen-fold increase in concentration of DAS-FITC-dextran-PLGA nanoparticles was observed compared to non-conjugated nanoparticles.
• The in vitro BBB model demonstrated high fidelity in replicating in vivo barrier properties.

Conclusions:

• DAS-conjugated PLGA nanoparticles are effective for targeted drug delivery across the BBB via RMT.
• The developed in vitro BBB model serves as a viable high-throughput screening platform for CNS therapeutics.
• This approach facilitates the advancement of promising therapeutic delivery systems for neurological diseases to in vivo studies.