“右旋糖酐-磁性层状复合氢氧化物-氟尿嘧啶”给药系统的超分子组装与磁靶向缓释作用

Supra-molecular assembly and magnetic targeted slow-release effect of "dextran-magnetic layered double hydroxide-fluorouracil" drug delivery system

用"共沉淀插层-原位复合-溶剂转换"技术合成"右旋糖酐-磁性层状复合氢氧化物-氟尿嘧啶"(dextran-magnetic layered double hydroxide-fluorouracil,DMF)载药系统,通过X射线粉末衍射(X-ray diffraction,XRD)、红外光谱(infrared spectrum,IR)、透射电镜(transmission electron microscopy,TEM)及热重分析(thermogravimetry,TG)表征及体外释放实验研究DMF的物相特征及缓释性能,通过动物实验考察DMF的体内靶向转运与缓释效果。结果表明,DMF的XRD与R-六方层状复合氢氧化物(layered double hydroxide,LDH)及Fd-3m立方铁氧体衍射特征吻合,IR证明DMF是右旋糖酐(dextran,DET)、磁性层状复合氢氧化物(magneticlayered double hydroxide,MLDH)及氟尿嘧啶(fluorouracil,FU)3种组分的超分子复合物;MLDH-FU具有六边菱形、层状特征,DET能保护MLDH-FU的层状结构、改善粒子分散性能、强化运载系统的缓释性能;体外pH 7.35 PBS环境中DMF的药物释放遵守零级模型C=1.171 6×10-5+4.462 6×10-7 t。DMF能在动物体内实现药物对靶区组织的优势转运,表现局域效应、靶向特异性及优异的循环转运性能;DMF的药动学过程表现峰值衰减、周期增长的多峰现象,达峰时间依次为给药后0.25、1、3、5、9天;首峰药动学方程CFU=14.34 e-0.530 t+36.04 e-0.321 t+24.18 e-0.196 t,吸收慢、消除快;后续药峰的半衰期增长、生物利用度提高、消除率降低;DMF的最高药峰值是原药的1/37,生物利用度是原药的419%。

The drug-loading system of DMF（dextran-magnetic layered double hydroxide-fluorouracil） was synthesized by ＂co-precipitation intercalated assembly-dextran composite in situ-solvent conversion＂ technology.The crystal-phase characteristic and slow-release performance of DMF were investigated through X-ray diffraction（XRD）,infrared spectrum（IR）,transmission electron microscopy（TEM）,thermogravimetry（TG） and in vitro release experiment.The targeted transshipment and slow-release effect of DMF system were evaluated by in vivo animal experiment.It was showed that the XRD of DMF matched with R-sixtetragonum type layered double hydroxide and Fd-3m cubic type ferrite.IR test demonstrated that the DMF system was a supra-molecular complex consisted of Dextran（DET）,magnetic layered double hydroxide（MLDH） and fluorouracil（FU） components.The two-level supra-molecular MLDH-FU presented six-edge lozenge TEM morphology,with layered characteristics.DET on the surface of DMF was capable of protecting the layered structure of MLDH-FU,improving particle dispersion properties,and strengthening the slow-release performance of the drug delivery system.The drug release model of DMF at pH 7.35 of PBS in vitro fit to the zero-order kinetics equation C = 1.171 6 × 10-5 ＋ 4.462 6 × 10-7 t.The drug delivery system DMF could transport drugs principally to in vivo target organs with a local effect,targeted specificity,and excellent circulation transshipment performance.The pharmacokinetic process of DMF presented multi-peak phenomenon with peak attenuation and cyclic growth.The peaks appeared at 0.25,1,3,5 and 9 d separately after dosing intervention.The first peak process of DMF accorded with a pharmacokinetic equation of CFU = 14.34 e-0.530 t ＋ 36.04 e-0.321 t ＋ 24.18 e-0.196 t,and presented the characteristic of slow absorption and fast elimination.As for subsequent peak processes,half-life increased,bioavailability increased,and plasma clearance decreased.The highest peak value of DMF was 1/37 of original value of FU,and the relative bioavailability was 419% to original FU.