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-shell type， 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±8.9nm，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±7.58ng·mL-1、120.00 min和（26 320.88±1 007.74ng·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。
Abstract
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 spectrophotometry 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 ρmax， tmax and AUC0-∞ were (89.26±7.58 ng·mL-1， 120.00 min and (26 320.88±1 007.74 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
{{custom_keyword}} /
Key words
neurotoxin /
self-assembled nanoparticles /
poly(ethylene glycol-g-polyethylcy-anoacrylate block copolymer /
intranasal administration /
brain pharmacokinetics /
brain microdialysis
{{custom_keyword}} /
柳琳 赵燕敏 李范珠.
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[J]. 中国药学杂志, 2011, 46(3): 203-207
LIU Lin;ZHO Yn-min;LI Fn-zhu.
Brain Pharmacokinetics of Self-Assembled Neurotoxin-Loaded Nanoparticles after Intranasal Administration in Rats[J]. Chinese Pharmaceutical Journal, 2011, 46(3): 203-207
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] CHEN R Z， ROBINSON S E. The effect of cholinergic manipulations on the analgesic response to cobrotoxin in cobrotoxin in mice[J]. Life Sci， 1990， 47(21： 1945-1954.
[2] CHEN R Z， WU X R. The analgesic action of cobra neurotoxin [J]. Chin Pharmacol Bull(中国药理学通报， 1988， 4(2： 113-116.
[3] LU Q M， MENG Q X， LI D S， et al. Comparative study of three short-chain neurotoxins from the venom of Naja kaouthia (Yunnan， China [J]. J Nat Toxins， 2002， 11(3： 221-229.
[4] FENG J， LI F Z. Advances on transnasal absorption enhancement of peptide and protein drugs [J]. Chin Pharm J (中国药学杂志， 2005， 40(15： 1128-1130.
[5] RUCKENSTEIN E， LI Z F. Surface modification and functionalization through the self-assembled monolayer and graft polymerization[J]. Adv Colloid Interface Sci， 2005， 113(1： 43-63.
[6] DONG A J. Polyglycol grafted and modified cyanoacrylate copolymer and its prepn. China， 02148633.6 [P]. 2003-05-14.
[7] YIGUANG J， LI T C， PING A， et al. Self-assembled drug delivery systems 1. Properties and in vitro/in vivo behavior of acyclovir self-assembled nanoparticles(SAN[J]. Inter J Pharm， 2006， 309 (1-2： 199-207.
[8] LIU L， XU L Z， LI F Z， et al. Preparation and in vitro release of self-assembled neurotoxin-loaded nanoparticles of core-shell type[J]. Chin Pharm J(中国药学杂志， 2009， 44(14： 1084-1088.
[9] CHEN S， XU Y， XU F， et al. Separation and determination of amino acids by micellar electrokinetic chromatography coupling with novel multiphoton excited fluorescence detection[J]. J Chromatogr A， 2007， 1162(2： 149-153.
[10] BAGGER M A， BECHGAARD E. The potential of nasal application for delivery to the central brain-a microdialysis study of fluorescein in rats[J]. Eur J Pharm Sci， 2004， 21(2-3： 235-242.
[11] KREUTER J， RAMGE P， PETROV V， et al. Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles[J]. Pharm Res， 2003， 20(3： 409-416.
[12] ANDRIEUX K， COUVREUR P. Polyalkylcyanoacrylate nanoparticles for delivery of drugs across the blood-brain barrier[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol， 2009， 1(5： 463-474.
[13] ESMAIEL J. Targeted delivery with peptidomimetic conjugated self-assembled nanoparticles[J]. Pharm Res， 2009， 26(3： 612-630.
[14] BASBAUM A I， FIELDS H L. Endogenous pain control system： brainstem spinal pathway and endorphin circuit [J]. Annu Rev Neurosci， 1984， 7：309-338.
[15] MASON P. Deconstructing endogenous pain modulations[J]. J Neurophysiol， 2005， 94(3：1659-1663.
[16] LI F， FENG J， CHENG Q， et al. Delivery of 125I-cobrotoxin after intranasal admi-nistration to the brain： a microdialysis study in freely-moving rats[J]. Int J Pharm， 2006， 328(2： 161-167.
[17] FIELDS H L， HEINRICHER M M， MASON P. Neurotransmitters in nociceptive modulatory circuits[J]. Annu Rev Neurosci， 1991， 14： 219-245.
[18] PAN Y F， FENG J， LI F Z， et al. Intracerebral microdialysis technique and its application on brain pharmacokinetic-pharmacodynamic study[J]. Arch Pharm Res， 2007，30(12： 1635-1645.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
PDF(805 KB)
