PEG-PE载药胶束的体内分布与毒性研究

Study of the biodistribution and toxicity of doxorubicin encapsulated in PEG-PE micelles in mice

目的:研究PEG-PE载药胶束静脉给药后在动物体内的分布与毒性。方法:采用一步自组装法制备载阿霉素的单一PEG-PE胶束或加入卵磷脂(HSPC)的混合胶束(M-Doxs);用BALB/c小鼠考察PEG-PE载药胶束的体内分布以及对动物生化指标及脏器的影响。结果:制备了3种不同粒径的载药胶束:M1-Dox[PEG-PE/HSPC=1∶0,(14.5±1.2)nm]、M2-Dox[PEG-PE/HSPC=1∶0.5,(22.4±0.9)nm]与M3-Dox[PEG-PE/HSPC=1∶1,(34.2±1.3)nm]。加入HSPC后胶束的形貌由球形逐渐变为棒状结构。M-Doxs在肝、肺、肾及肿瘤中的分布呈粒径依赖性。在22.5 mg.kg-1剂量下,M1-Dox与M3-Dox组的动物生存期明显延长。M-Doxs可显著降低对动物的全身毒性。结论:粒子的大小与形貌可改变M-Doxs在体内的分布,减轻药物的全身毒性。通过对纳米载药系统的物理化学性质进行修饰,可改变其在体内的行为。

Objective：To investigate the biodistribution and acute toxicity of doxorubicin loaded in PEG-PE based micelles（M-Doxs）for mice through the tail vein injection.Methods： Doxorubicin was loaded in the simple or mixed micelles made from polyethylene glycol-phosphatidylethanolamine alone（PEG-PE）or combined with hydrogenated phosphatidylcholine（HSPC）by a self-assembly procedure.Different doses of free doxorubicin（F-Dox）and equivalent doses of M-Doxs were intravenously in mice to compare their biodistribution and acute toxicities.Results： The increased molar ratios of HSPC in the PEG-PE based micelles increase the particle size（one dimension elongation）and change their shapes from the spherical to the worm like-rod.The mean sizes of M1-Dox（PEG-PE/HSPC=1∶0）,M2-Dox（PEG-PE/HSPC=1∶0.5）and M3-Dox（PEG-PE/HSPC=1∶1）are（14.5±1.2）nm,（22.4±0.9）nm,and（34.2±1.3）nm,respectively.Biodistribution of M-Doxs showed a significantly size and shape-depended accumulation in liver,lung,kidney and tumor.M1-Dox and M2-Dox exhibited higher drug concentration in serum and lymph node,while M1-Dox showed the lowest drug concentration in heart.Compared with F-Dox,M-Doxs had shown the low systemic toxicity.The survival time of mice in the groups of M1-Dox and M3-Dox was markedly prolongation compared with F-Dox at the dose of 22.5 mg·kg-1.Conclusion： The size and shape of doxorubicin loaded-micelles significantly influenced the behaviors,toxicity of doxorubicin in vivo.It is to be come true that controlling drug behavior in vivo by modifying the physicochemical properties of nano-carriers to implement diverse therapeutic requirements in clinic.