转铁蛋白修饰的辣蓼黄酮脂质体的药代动力学和脑靶向性研究  

Pharmacokinetic and Brain Targeting Study of Transferrin-Modified Polygonum hydropiper L.Flavonoid Liposomes

作　　者：吴昌旭 张金武 彭春子 吕茂杰 杨世森 韦英益[1] 陈海兰[1] 何家康[1] 胡庭俊[1] 于美玲 WU Changxu;ZHANG Jinwu;PENG Chunzi;LYU Maojie;YANG Shisen;WEI Yingyi;CHEN Hailan;HE Jiakang;HU Tingjun;YU Meiling(College of Animal Science and Technology,Guangxi University,Nanning 530004,China)

机构地区：[1]广西大学动物科学技术学院,广西南宁530004

出　　处：《中国兽医杂志》2025年第4期1-10,共10页Chinese Journal of Veterinary Medicine

基　　金：国家自然科学基金项目(32202850,32360894);广西自然科学基金面上基金项目(2021GXNSFAA196004);广西大学自然科学与技术创新发展倍增计划项目(2024BZRC013)。

摘　　要：为了探究转铁蛋白(Tf)修饰的辣蓼黄酮(FPHL)脂质体(Tf-FPHL-Lip)的药代动力学特征并明确Tf修饰对脂质体(Lip)体内外血脑屏障(BBB)透过能力的影响,本试验建立大鼠血浆中FPHL的芦丁成分含量测定的高效液相色谱(HPLC)分析方法,分析Tf-FPHL-Lip在大鼠体内的药代动力学特征;利用小鼠脑微血管内皮细胞(bEnd3)和小脑星形胶质细胞(C8-D1A)建立体外BBB模型,考察Lip透过体外BBB的能力;将Tf-FPHL-Lip经尾静脉注射小鼠,通过小动物活体成像技术观察荧光标记的Lip在小鼠体内的分布,考察Tf-FPHL-Lip透过体内BBB的能力。结果显示,建立的大鼠血浆中芦丁含量测定的HPLC分析方法的专属性、线性、回收率和精密度等均满足药动学分析方法的要求。与FPHL组相比,FPHL-Lip组和Tf-FPHLLip组的达峰浓度(C_(max))、血药浓度-时间曲线下面积(从0到无穷大)(AUC_(0-∞))、血药浓度-时间曲线下面积(从0到t)(AUC_(0-t))、平均驻留时间(MRT_(0-∞))和半衰期(T_(1/2))均极显著升高(P<0.01),清除率(CL)极显著降低(P <0.01);Tf-FPHL-Lip组的C_(max)、AUC_(0-∞)、AUC_(0-t)、MRT_(0-∞)和T_(1/2)分别为FPHL-Lip组的1.12、1.17、1.16、1.01和1.03倍;Tf-FPHL-Lip组的药时曲线下的峰面积最大,而FPHL组的药时曲线下的峰面积最小。Tf修饰的罗丹明B(RhB)脂质体(Tf-RhB-Lip)组在Transwell小室下层荧光信号强度极显著高于罗丹明B脂质体(RhB-Lip)组(P <0.01),表明Lip经Tf修饰后可以透过体外BBB。Tf修饰的吲哚箐绿(ICG)脂质体(Tf-ICG-Lip)组小鼠脑部荧光信号强度极显著高于吲哚箐绿脂质体(ICG-Lip)组和ICG组(P <0.01),并且维持时间长达36 h,表明Lip经Tf修饰后可以透过体内BBB。综上,Tf修饰可促进脂质体药物透过体内外BBB,增加脂质体药物体内吸收,Tf-FPHL-Lip具有一定的缓释作用。本试验结果为Tf-FPHL-Lip的脑部递送提供理论基础,为临床用药提供理论依据。To investigate the pharmacokinetic characteristics of transferrin(Tf)-modified flavonoid of Polygonum hydropiper L.(FPHL)liposomes(Tf-FPHL-Lip)and to clarify the effect of Tf modification on liposome permeability across the blood-brain barrier(BBB)both in vitro and in vivo,this study established a high-performance liquid chromatography(HPLC)method for the determination of rutin concentration in rat plasma and analyzed the pharmacokinetics of Tf-FPHL-Lip in rats.An in vitro BBB model was constructed using mouse brain microvascular endothelial cells(bEnd3)and cerebellar astrocytes(C8-D1A)to evaluate the permeability of Lip across the BBB.Additionally,Tf-FPHL-Lip was administered to mice via tail vein injection,and the distribution of fluorescently labeled Lip in vivo was observed using small animal live imaging technology to assess the BBB permeability of Tf-FPHL-Lip in vivo.The results demonstrated that the established HPLC method met the requirements for pharmacokinetic analysis in terms of specificity,linearity,recovery,and precision.Compared wtih the FPHL group,both FPHL-Lip and Tf-FPHL-Lip groups exhibited significantly increased peak plasma concentration(C_(max)),area under the plasma drug concentration-time curve from 0 to infinity(AUC_(0-∞)),area under the plasma drug concentration-time curve from time 0 to time t(AUC_(0-t)),mean residence time(MRT_(0-∞)),and half-life(T1/2)(P<0.01),while clearance(CL)was significantly reduced(P<0.01).The C_(max),AUC_(0-∞),AUC_(0-t),MRT_(0-∞),and T1/2 of the Tf-FPHL-Lip group were 1.12,1.17,1.16,1.01,and 1.03 times those of the FPHL-Lip group,respectively.The peak area under the plasma drug concentration-time curve was highest in the Tf-FPHL-Lip group and lowest in the FPHL group.In the Transwell assay,the fluorescence signal intensity in the lower chamber of the Tf-modified Rhodamine B(Tf-RhB-Lip)group was significantly higher than that of the Rhodamine B liposome(RhB-Lip)group(P<0.01),indicating enhanced BBB penetration in vitro following Tf modification.Similarly

关 键 词：转铁蛋白 辣蓼黄酮 脂质体 药代动力学 血脑屏障 

分 类 号：S859.53[农业科学—临床兽医学]