Brain-targeting study of stearic acid-grafted chitosan micelle drug-delivery system.
OBJECTIVE
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 μg/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 IC(50) of which was 237.6 ± 6.61 μg/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 μg/mL, compared with 0.181 ± 0.066 μg/mL of DOX · 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 · 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.


CONCLUSIONS
The CS-SA micelles were able to be used as a promising carrier for a braintargeting drug delivery system.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Yi-Ting
YT
Xie
Yong-Zhong
YZ
Du
Hong
H
Yuan
Fu-Qiang
FQ
Hu
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002461:Cell Line, Transformed; D048271:Chitosan / Q000737:chemistry* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D016650:Fluorescein-5-isothiocyanate; D051379:Mice; D008813:Mice, Inbred ICR; D008823:Micelles; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D013229:Stearic Acids / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D051598:Whole Body Imaging
D004337:Drug Carriers; D008823:Micelles; D013229:Stearic Acids; C031183:stearic acid; D004317:Doxorubicin; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate