Brain-targeting study of stearic acid-grafted chitosan micelle drug-delivery system

Purpose: Therapy for central nervous system disease is mainly restricted by the blood-brain barrier. A drug-delivery system is an effective approach to overcome this barrier. In this research, the potential of polymeric micelles for brain-targeting drug delivery was studied. Methods: Stearic acid-grafted chitosan (CS-SA) was synthesized by hydrophobic modification of chitosan with stearic acid. The physicochemical characteristics of CS-SA micelles were investigated. bEnd.3 cells were chosen as model cells to evaluate the internalization ability and cytotoxicity of CS-SA micelles in vitro. Doxorubicin (DOX), as a model drug, was physically encapsulated in CS-SA micelles. The in vivo brain-targeting ability of CS-SA micelles was qualitatively and quantitatively studied by in vivo imaging and high-performance liquid chromatography analysis, respectively. The therapeutic effect of DOX-loaded micelles in vitro was performed on glioma C6 cells. Results: The critical micelle concentration of CS-SA micelles with 26.9% +/- 1.08% amino substitute degree was 65 mu g/mL. The diameter and surface potential of synthesized CS-SA micelles in aqueous solution was 22 +/- 0.98 nm and 36.4 +/- 0.71 mV, respectively. CS-SA micelles presented excellent cellular uptake ability on bEnd.3 cells, the IC50 of which was 237.6 +/- 6.61 mu g/mL. DOX-loaded micelles exhibited slow drug-release behavior, with a cumulative release up to 72% within 48 hours in vitro. The cytotoxicity of DOX-loaded CS-SA micelles against C6 was 2.664 +/- 0.036 mu g/mL, compared with 0.181 +/- 0.066 mu g/mL of DOX center dot HCl. In vivo imaging results indicated that CS-SA was able to transport rapidly across the blood-brain barrier and into the brain. A maximum DOX distribution in brain of 1.01%/g was observed 15 minutes after administration and maintained above 0.45%/g within 1 hour. Meanwhile, free DOX center dot HCl was not detected in brain. In other major tissues, DOX-loaded micelles were mainly distributed into lung, liver, and spleen, with a reduction of DOX accumulation in heart. Conclusion: The CS-SA micelles were able to be used as a promising carrier for a brain-targeting drug delivery system.