One-step preparation of self-imaging Fe3O4@chitosan drug-loaded embolic microspheres by electrostatic spraying
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摘要:
经导管动脉栓塞术(TACE)是晚期肝细胞癌首选的治疗方案，目前栓塞剂的研究热点主要围绕着降低手术操作难度和提高TACE治疗效果，自显影栓塞剂可以在TACE术时精确反馈所在位置和手术后疗效监测，但自显影栓塞剂制备工艺繁杂，往往需多步合成。另外，目前大多的研究都集中在小尺寸(<300 µm)微球的制备，而临床实践中广泛使用的栓塞微球的直径范围为75至900 µm，并且传统的微球成型工艺制备微球粒径分布较大(±100 μm)，还需进一步分筛后使用。因此，有必要开发一种简便的方法来制备尺寸范围大，粒径均匀可控的自显影栓塞微球。采用静电喷雾法实现了造影剂Fe3O4NPs与壳聚糖微球同时合成，Fe3O4NPs被均匀地包裹在微球中。通过改变电喷雾参数，实现直径范围90至1000 μm粒径均匀微球的按需制备，制备的Fe3O4@CS微球具备临床磁共振成像、可降解和药物负载能力。 (a)Fe3O4@CS微球的SEM图像，(b)Fe3O4@CS微球的磁共振成像图，(c)载药Fe3O4@CS微球的荧光成像图。 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 are biodegradable, Magnetic resonance imaging showed that the prepared Fe3O4@CS microspheres have excellent clinical imaging capabilities. Moreover, blood and cytocompatibility assessments confirmed the good biocompatibility of Fe3O4@CS microspheres. The drug-loaded microspheres loaded with DOX showed a typical drug sustained release curve, and the cumulative release rate of DOX was 28.82% within 72 hours. These results demonstrated that one-step controllable preparation of self-imaging embolic agents showed great potential for future applications in transcatheter arterial embolization (TACE). -
图 1 (a)Fe3O4@壳聚糖(CS)微球的SEM图像，(b)(c)分别为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 images of Fe3O4@Chitosan (CS) microspheres, (b) and(c) The optical microscope images of 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 3 Fe3O4@CS微球的XRD图(蓝线参考JCPDS数据库Fe3O4NPs的XRD谱图)
Figure 3. The XRD patterns of Fe3O4NPs (the blue line referring to the JCPDS database);
图 4 Fe3O4@CS微球截面SEM-EDX图
Figure 4. SEM-EDX image 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 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HUVEC细胞的细胞毒性
Figure 8. cytotoxicity of various Fe3O4@CS microsphere concentrations on 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微球对癌细胞杀伤力评价；(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, and (c) drug release in vitro of drug-loaded Fe3O4@CS microspheres; (d) The 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.
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