神经毒素自组装核壳型纳米粒大鼠鼻黏膜给药脑内药动学研究  

Brain Pharmacokinetics of Self-Assembled Neurotoxin-Loaded Nanoparticles after Intranasal Administration in Rats

作　　者：柳琳[1] 赵燕敏[2] 李范珠[2] 

机构地区：[1]浙江大学医学院附属第一医院药剂科,杭州310003 [2]浙江中医药大学药学院,杭州310053

出　　处：《中国药学杂志》2011年第3期203-207,共5页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(30772793);浙江省卫生高层次创新人才培养工程

摘　　要：目的考察亲水性多肽类药物神经毒素自组装核壳型纳米粒(self-assembled neurotoxin-loaded nanoparticles of core-shelltype,NT-SAN)大鼠鼻黏膜给药后脑内药动学特征。方法以异硫氰酸荧光素标记NT(FITC-NT),采用聚乙二醇-g-聚氰基丙烯酸乙酯嵌段共聚物(PEG-g-PECA)为载体,乳化聚合法制备FITC-NT-SAN。采用大鼠脑微透析技术及荧光分光光度法,以FITC-NT-SAN和FITC-NT溶液肌内注射给药为对照,连续测定FITC-NT-SAN经鼻黏膜给药后FITC-NT在大鼠中脑导水管周围灰质(periaqueductal gray,PAG)部位浓度的经时变化。结果 FITC-NT-SAN呈圆形或类圆形,大小均匀,平均粒径为(89.6±8.9)nm,包封率为(58.43±0.62)%。FITC-NT-SAN经鼻黏膜给药后在PAG的FITC-NT浓度均明显高于FITC-NT-SAN和FITC-NT溶液的肌内注射给药(P<0.01),ρmax、tmax和AUC0-∞分别为(89.26±7.58)ng.mL-1、120.00 min和(26 320.88±1 007.74)ng.min.mL-1,相对生物利用度为137.28%。结论以PEG-g-PECA为载体的FITC-NT-SAN经鼻黏膜给药有助于提高NT的脑内浓度及生物利用度,该结果为研究适宜蛋白质多肽类等大分子药物经鼻黏膜给药的脑靶向新剂型提供参考。OBJECTIVE To investigate the brain pharmacokinetic profile of the self-assembled neurotoxin-loaded nanoparticles （NT-SAN） after intranasal administration in rats. METHODS FITC- NT-SAN（ NT labeled with fluorescein isothiocyanate） were prepared with PEG-g-PECA by emulsion polymerization method. Using intracerebral microdialysis sampling technique in awake freely-moving rats, the fluorescence value of dialysates in PAG were measured by fluorescence spectruphotometry after intranasal administrating FITC- NT-SAN in rats. After converting fluorescence value into corresponding concentrations of FITC-NT by in vivo recovery of microdialysis probes, the pharmacokinetic parameters were calculated. RESULTS The nanoparticles were formed with mean diameter of （89. 6 ± 8.9） nm and entrapment efficiency of （58.43 ± 0. 62） %. The concentrations of FITC-NT in PAG after intranasal administrating FITC- NT-SAN were significantly increased compared with FITC-NT-SAN after intramuscular injection （im.） or FITC-NT solution im. （P 〈 0.01）, and the parameters of pmax and AUC0-∞ were （89.26±7.58） ng . mL-1, 120. 00 min and （26 320.88 ±1007.74） ng . min . mL -1, respectively. The bioavailability was 137. 28%. CONCLUSION FITC-NT-SAN might be a potential new NT carrier for intranasal administration. It provides a feasible path for the administration of macro-molecule drug such as protein and polypeptide.

关 键 词：神经毒素 自组装核壳型纳米粒 聚乙二醇-g-聚氰基丙烯酸乙酯嵌段共聚物 鼻黏膜给药 脑内药动学 脑微透析技术 

分 类 号：R944[医药卫生—药剂学]