Influence of nanoparticle size on blood-brain barrier penetration and the accumulation of anti-seizure medicines in the brain

Anti-seizure medicines constitute a common yet important modality to treat epilepsy. However, some of them are associated with serious side effects including hepatotoxicity and hypersensitivity. Furthermore, the blood-brain barrier (BBB) is an insurmountable obstacle for brain drug delivery. Fortunately, the introduction of the nanoparticles for drug delivery is a feasible approach to overcome these obstacles. Encapsulating drugs into nanoparticles and delivering them to specific sites shows great potential in improving the efficiency of drug delivery and reducing systemic toxicity. Several in vivo studies have investigated the effect of nanoparticle size on biodistribution in mice, but very few have investigated its effects in efficient drug delivery while crossing the BBB. Therefore, we designed a methoxy poly (lactide-co-glycolide)-b-poly(ethylene glycol) methyl ether (mPEG-PLGA) nanoparticle delivery system and explored the cell uptake efficiency of nanoparticles with different sizes and their ability to penetrate the BBB while carrying carbamazepine (CBZ). CBZ-loaded nanoparticles could significantly reduce the cytotoxicity of CBZ to L929 cells at high concentrations. Results from the endocytosis experiment involving human cerebral microvessel endothelial cell/D3 showed that the DiR-loaded mPEG5K-PLGA10K nanoparticles possessed the highest cell uptake efficiency. The endocytosis efficiency was 90% at 30 min, which far exceeded that of the other groups. Moreover, similar results were obtained from subsequent experiments where fluorescent images of the isolated organs of the mice were acquired. To summarize, our study demonstrated that drug delivery to the brain using nanocarriers is size dependent. Nanoparticles with the smallest particle size could be internalized more effectively, easily penetrate the BBB, and accumulate in the brain.