Gemini quaternary ammonium-incorporated biodegradable multiblock polyurethane micelles for brain drug delivery

Abstract

Brain drug delivery is still facing significant challenges due to the low permeability of the blood–brain barrier (BBB). To overcome such an insurmountable obstacle, we developed gemini quaternary ammonium (GQA) as a cell penetrating molecule incorporated into biodegradable multiblock poly(ε-caprolactone urethanes)s (BMPUs) drug nanocarriers for improvement of drug accumulation in brain parenchyma. The zeta potential of Dox-loaded GQA-BMPUs micelles was around 26 mV with a mean particle size near 100 nm. It was found that GQA-BMPUs micelles achieved steadily time-dependent and concentration-dependent Dox accumulation in human brain microvascular endothelial cells (HBMECs) much higher than GQA-free BMPUs micelles and free Dox, as confirmed by flow cytometry and confocal laser scanning microscopy (CLSM) experiments. Meanwhile, no pronounced cytotoxicity was noticed in GQA-BMPUs micelles and GQA-free BMPUs micelles, and Dox associated cytotoxicity might be reduced once encapsulated into micelles. More importantly, CLSM of brain sections showed higher accumulation of Dox-loaded GQA-BMPUs micelles in the subcortical area after administrated intravenously, while no Dox accumulation was observed in either Dox-BMPUs micelles or free Dox formulation. Coupling with in vivo pharmacokinetics, biodistribution and histological toxicity studies, the results show that GQA introduced into drug nanocarriers is a promising avenue to transport therapeutic agents across BBB and improve brain drug accumulation.