肿瘤靶向纳米四氧化三铁造影剂的制备及其磁共振成像应用

Preparation of Tumor Targeting SPIO and Its Application in MRI

环氧氯丙烷交联法制备交联葡聚糖与多肽偶联的肿瘤新生血管靶向的纳米Fe3O4造影剂,考察其体内肿瘤靶向性并进行磁共振成像试验。以共沉淀法制备6～8nm的Fe3O4粒子,采用油酸钠和葡聚糖二次包覆,用环氧氯丙烷使葡聚糖交联并与靶向多肽偶联,进行了肿瘤细胞结合实验和荷瘤动物磁共振成像实验。结果表明,包覆后纳米Fe3O4复合粒子为20～30nm,水动力学粒径小于80nm,仍表现为超顺磁性;葡聚糖交联的时间4～8h,造影剂在体内血浆半衰期从2.8h延长到6.2h;主要通过肝脏和肾脏代谢。与无靶的比较,靶向多肽偶联后与肿瘤细胞特异性结合能力提高了10～30倍,MR成像信号密度是无靶的3.68倍。

Aqueous colloid containing Fe3O4 core nanoparticles coated by cross-linked dextran and angiogenesis-targeting peptide were synthesized and used as contrast agents for tumor-specific magnetic resonance imaging （MRI）. Fe3 O4 nanoparticles with sizes between 6 to 8 nm were crystallized in aqueous solution of oleate by alkaline coprecipitation method, and coated by dextran. Dextran was cross-linked with chloromethyloxirane in alkaline solution at pH 13, and then coupled with peptides in carbonate buffer solution with pH 10. Results show that the composite nanoparticles are superparamagnetic with the overall sizes between 20 to 30 nm and their hydrodynamic diameter below 80 nm. Plasma half-life is increased from 2.8 hours （no cross-linked） to 6.2 hours after cross-linking, and their main metabolism is through liver and kidney. The superparamagnetic iron oxide （SPIO） composite coupled with double targeting peptides yield that the concentration of Fe3＋ in human lung adenoearcinoma cells A549 increases 10 to 30 times, and that tumor MRI signal density in xenogragft of the nude mice increases 3.86 times compared with that without peptide.