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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柳琳,赵燕敏,李范珠(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)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-assembledneurotoxin—loadednanoparticlesofcore—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),采用聚乙二醇一g一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(periaqueductalgray,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±o.62)%。FITC—NT—SAN经鼻黏膜给药后在PAG的FITC—NT浓度均明显高于nTC—NT—SAN和FITC—NT溶液的肌内注射给药(P<0.01),P⋯、t⋯和AUC0一分别为(89.26±7.58)ng‘mL、120.00min和(26320.88±1007.74)ng’min’mL,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。关键词:神经毒素;自组装核壳型纳米粒;聚乙二醇一g一聚氰基丙烯酸乙酯嵌段共聚物;鼻黏膜给药;脑内药动学;脑微透析技术中图分类号:R944文献标志码:A文章编号:1001—2494(2011)03—0203—05BrainPharmacokineticsofSelf-AssembledNeurotoxin-LoadedNanoparticlesafterIntranasaiAdministra·-tioninRatsLIULin,ZHAOYah—rain,LIFan—zhu。(1.DepartmentofPharmacol。gY,FirstAffiliatedHospital,ZhejiⅡngUniversitySch。。1ofMedicine,Hangzhou310003,China:2.CollegeofPharmaceuticalScience,ChineseMedicalUniversity,Hangzhou310053,China)ABSTRACT:OBJECTIVEToinvestigatethebrainpharmacokineticprofileoftheself-assembledneurotoxin—loadednanoparticles(NT—SAN)afterintranasaladnfinistrationinrats.METHODSFITC—NT—SAN(NTlabeledwithfluoresceinisothiocyanate)werepre—paredwithPEG—g—PECAbyemulsionpolymerizationmethod.Usingintracerebralmicrodialysissamplingtechniqueinawakefreely—movingrats,thefluorescencevalueafdialysatesinPAGweremeasuredbyfluorescencespectrophotometryafterintranasaladministratingFITC—NT—SANinrats.AfterconvertingfluorescencevalueintocorrespondingconcentrationsofFITC—NTbyinvivorecoveryofmicrodialysisprobes,thepharmaeokineticparameterswerecalculated.RESULTSThenanoparticleswereformedwithmeandiameterof(89.6±8.9)nmandentrapmenteficiencyof(58.43±0.62)%.TheconcentrationsofFITC—NTinPAGafterintranasaladministratingFITC—NT—SANweresignificantlyincrease