脑靶向性研究硬脂酸接枝壳聚糖胶束给药系统。

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

机构信息

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

出版信息

Int J Nanomedicine. 2012;7:3235-44. doi: 10.2147/IJN.S32701. Epub 2012 Jun 29.

DOI:10.2147/IJN.S32701

PMID:22802685

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3396390/

Abstract

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 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.

CONCLUSION

The CS-SA micelles were able to be used as a promising carrier for a braintargeting drug delivery system.

摘要

目的

中枢神经系统疾病的治疗主要受到血脑屏障的限制。药物传递系统是克服这一障碍的有效方法。本研究探讨了聚合物胶束作为脑靶向药物传递的潜力。

方法

通过硬脂酸对壳聚糖（CS-SA）进行疏水改性合成。研究了 CS-SA 胶束的理化特性。bEnd.3 细胞被选为模型细胞，用于评估 CS-SA 胶束在体外的内化能力和细胞毒性。阿霉素（DOX）作为模型药物被物理包封在 CS-SA 胶束中。通过体内成像和高效液相色谱分析分别定性和定量研究 CS-SA 胶束的体内脑靶向能力。在体外，对载药胶束对神经胶质瘤 C6 细胞的治疗效果进行了研究。

结果

具有 26.9%±1.08%氨基取代度的 CS-SA 胶束的临界胶束浓度为 65μg/mL。在水溶液中合成的 CS-SA 胶束的直径和表面电位分别为 22±0.98nm 和 36.4±0.71mV。CS-SA 胶束对 bEnd.3 细胞具有优异的细胞摄取能力，IC50 为 237.6±6.61μg/mL。载药胶束表现出缓慢的药物释放行为，体外 48 小时内累积释放达到 72%。载药 CS-SA 胶束对 C6 的细胞毒性为 2.664±0.036μg/mL，而 DOX·HCl 的细胞毒性为 0.181±0.066μg/mL。体内成像结果表明，CS-SA 能够快速穿过血脑屏障并进入大脑。给药后 15 分钟观察到大脑中 DOX 的最大分布为 1.01%/g，并在 1 小时内保持在 0.45%/g 以上。同时，在脑中未检测到游离的 DOX·HCl。在其他主要组织中，载药胶束主要分布在肺、肝和脾中，心脏中 DOX 的积累减少。