载阿霉素纳米粒温敏凝胶的制备及评价

Preparation and evaluation of doxorubicin-loaded nanoparticles thermosensitive gel

目的 对制备出可用于肝动脉化疗栓塞(TACE)的载阿霉素纳米粒温敏凝胶(DOX-NPs-Gel)复合体系的相关特性进行评价。方法 以乳酸-羟基乙酸共聚物(PLGA)为载体,采用复乳法制备载阿霉素纳米粒(DOX-NPs),考察其外观、粒径、PDI和Zeta电位,经冷冻干燥得DOX-NPs冻干粉,将其分散于壳聚糖(CS)/β-甘油磷酸(β-GP)温敏凝胶(Gel),制得DOX-NPs-Gel;采用倒瓶法考察Gel、DOX-Gel、空白-NPs-Gel及DOX-NPs-Gel在37℃下的胶凝化时间及胶凝温度;扫描电镜观察微观结构;通过兔耳中动脉栓塞实验考察了空白-NPs-Gel的栓塞性能;通过在皮下注射空白-NPs-Gel于不同时间脱颈死小鼠,剥离出空白-NPs-Gel,测量其大小及质量,评价其吸收特性;采用动态膜透析法考察DOX、DOX-NPs、DOX-Gel的体外释放;采用无膜溶出法考察DOX-NPs-Gel的体外释放。结果 制备出的DOX-NPs形态规则,粒径为(186.68±5.99)nm,多分散系数(PDI)为(0.17±0.01),Zeta电位为(-23.33±1.54)mV,包封率和载药量分别为(77.10±4.46)%和(2.64±0.19)%;DOX-NPs-Gel 37℃下胶凝化时间为(165±15)s,胶凝化温度为(34.67±0.47)℃,冻干后其微观结构为整齐紧密的多孔结构;该复合体系可顺利通过微导管注射,可栓塞兔耳中动脉,且在皮下可被缓慢吸收;体外释放结果显示,第7天时DOX-NPs-Gel中DOX和DOX-NPs的释放率分别为(6.15±0.19)%和(47.25±5.11)%。结论 本研究制备的DOX-NPs-Gel在体温下可快速胶凝、可栓塞血管和皮下吸收,能够缓慢释放DOX-NPs。

Objective To investigate related characteristics of doxorubicin-loaded nanoparticles thermosensitive gel(DOX-NPs-Gel)composite system for hepatic arterial chemoembolization(TACE).Methods Poly-lactic-co-glycolic acid(PLGA)as the carrier,doxorubicin-loaded nanoparticles(DOX-NPs)were prepared by double emulsion.The appearance,particle size,PDI and Zeta potential were investigated;DOX-NPs lyophilized powder was obtained,which was dispersed in chitosan(CS)/β-glycerophosphate(β-GP)thermosensitive gel(Gel)for DOX-NPs-Gel.Its gelling time and gelling temperature of Gel,DOX-Gel,Blank-NPs-Gel and DOX-NPs-Gel were examined by bottle-tumbling assay un the temperature of 37℃;microstructure was observed by scanning electron microscope;embolism function of Blank-NPs-Gel was investigated by Rabbit Ear Central Artery Embolism Experiment;subcutaneous injection of Blank-NPs-Gel was administered for mice death by neck dislocation at varied time points,then Blank-NPs-Gel was stripped for measurement and quality in order to evaluate its absorption features.Dynamic membrane dialysis was adopted to examine in vitro release of DOX,DOX-NPs,DOX-Gel;non-membrane dissolution assay was adopted to examine invitro release of DOX-NPs-Gel.Results The prepared DOX-NPs were morphologically regular,with a particle size of(186.68±5.99)nm,PDI of(0.17±0.01),Zeta potential of(-23.33±1.54)mV,encapsulation rate and drug load of(77.10±4.46)%and(2.64±0.19)%.The gelling time of DOX-NPs-Gel at 37℃was(165±15)s;gelling temperature was(34.67±0.47)℃.After lyophilization,its microstructure is neat and tightly porous.The composite system could be successfully injected through a microcatheter,which could successfully embolize the rabbit ear central artery and could be slowly absorbed subcutaneously.In vitro release results showed that the release rates of DOX and DOX-NPs in DOX-NPs-Gel at 7 th days were(6.15±0.19)%and(47.25±5.11)%.Conclusion The DOX-NPs-Gel prepared in this study can be rapidly gelling,embolizing blood vessels and be absorbed subcutaneously at body temperature.It can release DOX-NPs slowly.