One-step preparation of self-imaging Fe3O4@chitosan drug-loaded embolic microspheres by electrostatic spraying
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摘要: 采用静电喷雾法一步制备包裹着Fe3O4纳米粒子的壳聚糖复合微球(Fe3O4@CS微球)，实现Fe3O4纳米粒子与微球同时合成。还可以按需制备粒径范围为90~1000 μm的Fe3O4@CS微球，以满足不同部位血管的临床栓塞要求。SEM显示微球形貌均匀且粒径分布均一((94±3) μm)，体外降解实验证明了微球具有生物可降解性，磁共振成像测试表明所制备的Fe3O4@CS微球具有良好的临床成像能力，血液、细胞相容性评估证实Fe3O4@CS微球具有良好的生物相容性。负载盐酸阿霉素(DOX)的载药微球显示出典型的药物缓释曲线，72 h内DOX的累计释放率为28.82%。结果表明，这一步可控制备的自显影栓塞剂在经导管动脉栓塞术(TACE)未来应用中展示了巨大的潜力。Abstract: Chitosan composite microspheres encapsulating Fe3O4 nanoparticles (Fe3O4@CS microspheres) were prepared in one step by the electrostatic spraying, enabling simultaneous synthesis of Fe3O4 nanoparticles and microspheres. Additionally, Fe3O4@CS microspheres with particle sizes ranging from 90 to 1000 μm could be prepared on demand to meet the clinical embolization requirements of different blood vessels. SEM images showed that the microspheres were homogeneous in shape and uniform in size distribution ((94±3) μm). In vitro degradation experiments proved that the microspheres were biodegradable. Magnetic resonance imaging showed that the prepared Fe3O4@CS microspheres had excellent clinical imaging capabilities. Moreover, blood and cytocompatibility assessments confirmed the good biocompatibility of Fe3O4@CS microspheres. The drug-loaded microspheres loaded with doxorubicin hydrochloride (DOX) showed a typical drug sustained release curve, and the cumulative release rate of DOX was 28.82% within 72 h. These results demonstrate that one-step controllable preparation of self-imaging embolic agents show great potential for future applications in transcatheter arterial embolization (TACE).
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图 1 (a) Fe3O4@壳聚糖(CS)微球的SEM图像及粒径分布直方图；((b), (c)) 微球溶胀前后的光学显微镜图及粒径分布直方图
Figure 1. (a) SEM image and histogram of particle size distribution of Fe3O4@chitosan (CS) microspheres; ((b), (c)) Optical microscope images of Fe3O4@CS microspheres before and after swelling and particle size distribution histograms
图 2 不同参数对Fe3O4@CS微球直径的影响：(a) 电压；(b) 针头大小；(c) 注射速度
Figure 2. Effect of different parameters on Fe3O4@CS microsphere diameter: (a) Voltage; (b) Needle size; (c) Injection speed
图 4 Fe3O4@CS微球截面SEM-EDX图像
Figure 4. SEM-EDX images of Fe3O4@CS microsphere cross-section
图 6 (a) Fe3O4@CS微球在磁场存在下的迁移图；(b) Fe3O4@CS微球的磁滞曲线图；(c) Fe3O4@CS微球体外模型的T2加权核磁共振成像(MRI)图像
Figure 6. (a) Migration diagram of Fe3O4@CS microspheres in the presence of a magnetic field; (b) Hysteresis curve diagram of Fe3O4@CS microspheres; (c) T2-weighted magnetic resonance imaging (MRI) images of Fe3O4@CS microspheres in a vitro model
图 7 不同浓度Fe3O4@CS微球的溶血率(插图1、2、3、4、5为阳性对照、阴性对照、1、5、20 mg/mL微球)
Figure 7. Hemolysis rate of various Fe3O4@CS microsphere contents (Insets 1, 2, 3, 4 and 5 were positive controls, negative controls, 1 mg/mL, 5 mg/mL and 20 mg/mL microspheres, respectively)
图 8 不同浓度Fe3O4@CS微球对人脐静脉内皮细胞(HUVEC)的细胞毒性
Figure 8. cytotoxicity of various Fe3O4@CS microsphere concentrations on human umbilical vein endothelial cell (HUVEC) cells
图 9 (a) 载药Fe3O4@CS微球的荧光成像图；(b) 载药Fe3O4@CS微球的载药率；(c) 载药Fe3O4@CS微球的药物体外释放；(d) 载药Fe3O4@CS微球孵育HepG2细胞24 h和48 h的细胞活力；(e) HepG2癌细胞的活/死染色荧光成像测定
Figure 9. (a) Fluorescence imaging of drug-loaded Fe3O4@CS microspheres; (b) Drug-loading capacities; (c) Drug release in vitro of drug-loaded Fe3O4@CS microspheres; (d) Cell viability of HepG2 cells incubating with drug-loaded Fe3O4@CS microspheres at 24 h and 48 h; (e) Live/dead staining fluorescence imaging assay of HepG2 cancer cells
DOX—Doxorubicin hydrochloride; AM—Calcein-AM; PI—Propidium iodide; Q—Diffusion flux; R2—Correlation coefficient
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