Fe_3O_4纳米粒子的组织相容性及组织分布研究

Histocompatibility and distribution of ferroferric oxide nanoparticles

背景:Fe_3O_4纳米粒子是目前研究较多的靶向性纳米药物递呈系统,它可与抗肿瘤药物结合在一起,在外界磁场作用下,运载抗肿瘤药物靶向性到达肿瘤部位发挥抗肿瘤作用,其亚微粒可以到达远离磁源数厘米的肿瘤部位。目的:分析Fe_3O_4纳米粒子的组织相容性及在机体内的药物分布,及其在骨肉瘤化疗中作为药物载体的应用前景和存在问题。方法:使用Wistar大鼠,按10.0 mg/kg剂量,Fe_3O_4纳米粒子经鼠尾静脉推注后15,60,120 min处死,取各组织(肺、脑、心、肝脏、肾脏、后肢骨、骨骼肌),采用原子吸收光谱仪分析各组织单位质量的铁离子含量。将各时间点的各种组织作苏木精-伊红染色以观察组织形态变化。结果与结论:(1)在肝和肾组织Fe_3O_4纳米粒子浓度于15 min时达到峰值,给药后60 min和120 min检测到的肝和肾组织纳米粒子浓度虽呈下降趋势但仍然维持在较高水平,3个时间点Fe_3O_4纳米粒子浓度与对照组比较差异有显著性意义(P<0.05),提示Fe_3O_4纳米粒子在肝和肾中快速浓集并能较长时间存留;(2)在心、肺、骨骼肌和骨组织中Fe_3O_4纳米粒子浓度于15 min时达到峰值,但随后迅速下降。15 min时Fe_3O_4纳米粒子浓度与对照组比较差异有显著性意义(P<0.05),仅在骨组织代谢较慢,在60 min时与对照组比较差异仍有显著性意义(P<0.05),表明Fe_3O_4纳米粒子在这些血流灌注高的组织中虽能达到高浓度但存留时间短。唯有骨组织可以较长时间的维持Fe_3O_4纳米粒子的高浓度;(3)在脑组织中各时间点Fe_3O_4纳米粒子浓度与对照组比较差异无显著性意义(P>0.05),提示Wistar大鼠的血脑屏障可能对Fe_3O_4纳米粒子的穿透具有阻碍作用;(4)所有的组织通过苏木精-伊红染色后均未发现明显的改变;(5)结果表明,偶联油酸钠Fe_3O_4纳米粒子在机体组织中的分布受组织血流灌注和单核巨噬细胞系统的影响,且不能穿透血脑屏障。对各种组织均未发现有显著的影响。偶联油酸钠Fe_3O_4纳米粒子在肝、肾和骨组织内可以维持较长较高浓度,作为磁靶向热化疗载体治疗上述脏器的恶性肿瘤有重要的理论意义。

BACKGROUND：Ferroferric oxide （Fe3O4） nanoparticles are a research hotspot in drug delivery system, which can transport antineoplastic drugs to the lesion under external magnetic field. Additional y, its submicrons even can reach the tumor site several centimeters far away from the magnetic source. OBJECTIVE：To investigate the histocompatibility and in vivo distribution of Fe3O4 nanoparticles and to explore its application prospect and limitations as a drug carrier in the chemotherapy of osteosarcoma. METHODS：10.0 mg/kg Fe3O4 nanoparticles were administrated into Wistar rats via tail vein, then the rats were executed at 15, 60 and 120 minutes, respectively, and the rat lung, brain, heart, liver, kidney, hind limb and skeletal muscle were removed. The ferric ion content in each tissue was determined by atomic absorption spectrometer, and the morphological changes of different tissues were observed by hematoxylin-eosin staining at each time point. RESULTS AND CONCLUSION：After administrated for 15 minutes, the concentration of Fe3O4 nanoparticles in the liver and kidney reached peak, fol owed by a decrease at 60 and 120 minutes, but stil remained a high level. The concentration of Fe3O4 nanoparticles at three time points showed significant difference compared with the control group （P〈0.05）, demonstrating that the nanoparticles can be quickly enriched and long-term persistent in the liver and kidney. After administrated for 15 minutes, the concentration of Fe3O4 nanoparticles in the heart, lung, skeletal muscle and bone reached peak, which had significant difference compared with the control group （P〈0.05）, and significantly decreased subsequently except that in the bone. This significant difference stil displayed at 60 minutes between groups （P〈0.05）, indicating that the nanoparticle can reach a high concentration but persist short time in the high blood perfused tissues. Compared with the control group, the concentration of Fe3O4 nanoparticles in the brain tissue showed no significant difference at each time point （P〉0.05）, suggesting that the blood-brain barrier can inhibit the nanoparticle penetration. No overt morphological changes were found in each tissue after hematoxylin-eosin staining. In conclusion, the distribution of Fe3O4 nanoparticles conjugate sodium oleate in organism is influenced by the blood perfusion and mononuclear phagocyte system, and they cannot penetrate the blood-brain barrier and make no significant effect on tissues, but maintain a high level in the liver kidney and bone for a long-term, thus providing a theoretical basis for the drug delivery system in the magenetic hyperthermia therapy of malignant tumors.