叶酸分子靶向载顺铂磁性纳米药物制备及表征

背景：醛基化海藻酸钠具有良好的水溶性和组织相容性,利用其改性Fe3O4磁性纳米颗粒可增加表面活性和稳定性,叶酸的修饰可赋予载体分子靶向性。目的：制备具有叶酸受体靶向及磁靶向的载顺铂磁性纳米药物(CDDP-FA-ASA-MNPs)。方法：采用高碘酸钠氧化法制备醛基化海藻酸钠,叶酸的羧基经二环己基碳二亚胺和N-羟基琥珀酰亚胺活化后合成FA与双端氨基聚乙二醇的耦连产物FA-PEG,化学共沉淀法制备Fe3O4,海藻酸钠侧链含有大量羧基,85 ℃下与Fe3O4纳米颗粒表面的羟基形成化学键结合,然后通过雪夫氏碱将FA-PEG与醛基化海藻酸钠相连接,最后根据配位络合的原理,顺铂分子中的-Cl被海藻酸钠的羧基取代,形成稳定的叶酸和醛基化海藻酸钠改性载顺铂磁性纳米复合物。结果与结论：所制备的磁性纳米药物呈颗粒状,稳定分散于水溶液中,Fe3O4磁核平均粒径为(8.116±0.24) nm,流体力学直径为(110.9±1.7) nm,zeta电位为(-26.45±1.26) mV,最大饱和磁化强度为56.2 emu/g,顺铂包封率为(49.05±1.58)%,载药量为(14.31±0.49)%。体外实验证实,叶酸分子靶向载顺铂磁性纳米药物能被叶酸受体表达阳性的鼻咽癌细胞HNE-1和喉癌细胞Hep-2选择性摄取,而叶酸受体表达阴性的鼻咽癌细胞CNE-2则不摄取。提示所制备的CDDP-FA-ASA-MNPs具有良好的水溶性和稳定性,能被叶酸受体表达阳性的鼻咽癌和喉癌细胞摄取。

Preparation and characterization of folate targeting magnetic nanomedicine loaded with cisplatin

BACKGROUND:Based on its good water-solubility and histocompatibility, aldehyde sodium alginate (ASA) can be used as a modifier to improve surfactivity and stability of magnetic Fe3O4 nanoparticles. Folate acid (FA) can be used as a targeting molecule for carrier.OBJECTIVE:To prepare cisplatin (CDDP)-loaded magnetic nanomedicine (CDDP-FA-ASA-MNPs) with abilities of folate receptor targeting and magnetic targeting.METHODS:ASA was prepared from sodium alginate by sodium periodate oxidation. FA was activated by dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS), and coupled with diaminopolyethylene glycol [PEG (NH2)2] to prepare FA-PEG. Fe3O4 nanoparticles were prepared using the chemical coprecipitation method. The carboxyl group in side chain of ASA was combined with hydroxyl group in Fe3O4 nanoparticles at 85 ℃. And then FA-PEG was connected with ASA by Schiff’s base. Finally, -Cl in CDDP was replaced by hydroxyl group in ASA based on principles of coordination complex, so FA and ASA modified CDDP-loaded magnetic nanoparticles (MNPs) were prepared. RESULTS AND CONCLUSION:CDDP-FA-ASA-MNPs prepared by this method could distribute stably in aqueous solution. The mean diameter of Fe3O4 core was (8.116±0.24) nm, hydrodynamic diameter was (110.9±1.7) nm, Zeta potential was (-26.45± 1.26) mV, maximum saturation magnetization was 56.2 emu/g, CDDP encapsulation efficiency was (49.05±1.58)%, and drug loading property was (14.31±0.49)%. In vitro, CDDP-FA-ASA-MNPs were selectively uptaked by HNE-1 cells and Hep-2 cells which expressed folate receptors positively, but not uptaked by CNE-2 which expressed folate receptor negatively. CDDP-FA- ASA-MNPs prepared by this method have good water-solubility and stability. It can be uptaked by nasopharyngeal carcinoma cells and laryngeal carcinoma cells with folate receptors positively.