微流控法可控制备放射性壳聚糖栓塞微球  

Controllable preparation of radioactive chitosan embolic microspheres by microfluidic method

作　　者：邓璐 巨晓洁[1,2] 张文杰[3] 谢锐[1,2] 汪伟 刘壮[1,2] 潘大伟 褚良银[1,2] DENG Lu;JU Xiaojie;ZHANG Wenjie;XIE Rui;WANG Wei;LIU Zhuang;PAN Dawei;CHU Liangyin(School of Chemical Engineering,Sichuan University,Chengdu 610065,Sichuan,China;State Key Laboratory of Polymer Materials Engineering,Sichuan University,Chengdu 610065,Sichuan,China;Department of Nuclear Medicine,West China Hospital,Sichuan University,Chengdu 610041,Sichuan,China)

机构地区：[1]四川大学化学工程学院,四川成都610065 [2]四川大学高分子材料工程国家重点实验室,四川成都610065 [3]四川大学华西医院核医学科,四川成都610041

出　　处：《化工学报》2023年第4期1781-1794,F0001,共15页CIESC Journal

基　　金：国家自然科学基金项目(22078202,21991101)。

摘　　要：以壳聚糖(CS)为基材原料,京尼平为交联剂,采用液滴微流控法制备了粒径在20~90μm范围内精确可调的可用于内放射介入治疗的栓塞微球。首先,通过在CS微球上接枝螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)进行改性,制备DOTA-CS微球,使微球具有稳定的负载放射性核素镥-177(^(177)Lu)的能力。然后,通过DOTA与^(177)Lu稳定的螯合作用,制备了DOTA-CS-^(177)Lu微球。探究了制备过程中乳液模板和CS微球之间大小变化的规律,实现了对微球尺寸的精确预测和调控。所制备CS微球的直径变异系数均低于5%,尺寸均一,单分散性好,具有良好的溶胀性能与弹性。通过分析傅里叶变换红外光谱(FT-IR)、紫外可见吸收光谱(UVVis)与电感耦合等离子体质谱(ICP-MS)结果,得出1∶1(质量比)为DOTA与微球的最佳改性比例。扫描电子显微镜(SEM)结果表明DOTA改性对微球的形貌与结构无影响。血液相容性实验与细胞毒性实验的评价结果表明,DOTA改性前后的CS微球均表现出良好的生物相容性。模拟体内降解环境,CS微球在60 d内形貌与粒径无明显变化,仅弹性略有下降。薄层色谱(TLC)结果表明,DOTA-CS-^(177)Lu微球具有较高的放射化学纯度,并在15 d内保持良好的放射稳定性。上述研究结果表明,所制备DOTA-CS-^(177)Lu微球表现出了用于体内放疗栓塞治疗的优势与潜力。Using chitosan(CS)as the base material and genipin as the crosslinking agent,the embolic microspheres with particle size precisely adjustable in the range of 20—90μm are prepared by droplet microfluidic method for internal-radiation interventional therapy.First,DOTA-CS microspheres are prepared by grafting chelating agent 1,4,7,10-tetrazazacyclododecane-1,4,7,10-tetraacetic acid(DOTA)on CS microspheres,so that the microspheres have the ability to stably load radioactive lutetium-177(^(177)Lu).Then,DOTA-CS-^(177)Lu microspheres are prepared by the stable chelation of DOTA with^(177)Lu.The law of size change between the emulsion templates and CS microspheres during the preparation process is explored,and the precise prediction and regulation of microsphere size are realized.The diameter variation coefficients of the prepared CS microspheres are all lower than 5%,the size is uniform,the monodispersity is good,and the swelling performance and elasticity are good.In addition,the prepared microspheres have good swelling property and elasticity.By analyzing the results of Fourier transform infrared spectroscopy(FT-IR),ultraviolet-visible absorption spectroscopy(UV-Vis)and inductively coupled plasma mass spectrometry(ICP-MS),it is concluded that the optimal modification ratio between DOTA and CS microspheres is 1∶1(mass ratio).Scanning electron microscopy(SEM)results show that DOTA modification has no effect on the morphology and structure of CS microspheres.The results of blood compatibility test and cytotoxicity test show that the CS microspheres before and after DOTA modification have good biocompatibility.Simulating the in vivo degradation environment,the morphology and particle size of CS microspheres do not change significantly within 60 days,and only the elasticity decreases slightly.Thin layer chromatography(TLC)results show that DOTA-CS-^(177)Lu microspheres have high radiochemical purity and could maintain good radioactive stability within 15 days.These research results show that the prepared DOTA-CS-^(177

关 键 词：液滴微流控 壳聚糖微球 DOTA 放疗栓塞介入治疗 

分 类 号：TQ469[化学工程—制药化工] TB34[一般工业技术—材料科学与工程]