可塑性纳米羟基磷灰石/聚羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇庆大霉素释药系统研制

PREPARATION OF PLASTIC NANO-HYDROXYAPATITE/POLY(3-HYDROYYBUTYRATE-HYDROXYVALE- RATE) -POLYETHY LENE GLYCOL GENTAMICIN DRUG DELIVERY SYSTEM

目的研制可塑性纳米羟基磷灰石/聚羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇[nano-hydroxyapatite/poly(3-hydroxybutyrate-hydroxyvalerate)-polyethyleneglycol,nano-HA/PHBV-PEG]庆大霉素(gentamicin,GM)局部药物释放系统(drugdeliverysystem,DDS),为治疗骨髓炎提供一有效方法。方法以纤维蛋白胶为微球支架,nano-HA为GM载药核心,外包裹PHBV及PEG,制成可塑性nano-HA/PHBV-PEG-GM-DDS。电镜观察nano-HA、载药nano-HA和载药nano-HA/PHBV-PEG微球形貌特征。将可塑性nano-HA/PHBV-PEG-GM-DDS植入36只新西兰大白兔股骨内,术后12个不同时间点K-B法检测其血液、皮质骨和松质骨GM浓度,评价可塑性nano-HA/PHBV-PEG-GM-DDS体内释药效果。结果nano-HA呈短棒状,长度<60nm。载药nano-HA呈晶体自然凝聚状态,表面吸附大量GM,平均粒径为200.5nm。载药nano-HA/PHBV-PEG微球表面形态一致,为多孔皱缩结构,平均粒径为34.5μm。GM浓度与抑菌环直径呈线性相关,相关系数为0.998。术后第1天可塑性nano-HA/PHBV-PEG-GM-DDS周围皮质骨和松质骨中GM浓度分别为95.50±16.50μg/ml和80.20±13.80μg/ml,其后逐渐下降,致第56天时为5.60±1.60和5.10±1.30μg/ml,高于GM对金葡菌的最低抑菌浓度(2μg/ml)。结论可塑性nano-HA/PHBV-PEG-GM-DDS具有较好的体内缓释作用,临床上对于骨髓炎的治疗有应用前景。

Objective To develop the plastic nano-hydroxyapatite （nano-HA）/poly （3-hydroxybutyratehydroxyvalerate） - polyethylene glycol（PHBV-PEG） gentamicin （GM） drug delivery system（DDS）（nano-HA/PHBV- PEG-GM-DDS） for treating osteomyelitis and find its releasing character in vivo. Methods The plastic nano-HA/ PHBV- PEG-GM-DDS was prepared using nano-HA as the core carrier of GM, nano-HA with PHBV and PEG as coating and plastic fibrin glue（FG） as microsphere scaffold. The morphological features of nano-HA,drug loaded nano- HA and drug loaded nano-HA/PHBV-PEG microsphere were examined by electron microscope. The GM concentration in blood, cortex bone and cancellous bone was detected at 12 different time points by the method of K-B after the plastic nano-HA/PHBV-PEG-GM-DDS was implanted into the femora of 36 rabbits. Its GM releasing character was assayed in vivo. Results Nano-HA was similar to a blackjack, and its length was less than 60 nm. Drug loaded nano-HA appeared natural crystal condensate, of which surface adsorbed massive GM. The average grain diameter was 200. 5 nm. Drug loaded nano-HA/PHBV-PEG microsphere had a shrinkable porous structure, of which surface configuration was consistent. The average grain diameter was 34.5 μm. The GM concentration and the antibacterial annulus was in the linear correlation. The correlation coefficient was 0. 998. In cortex and cancellous bone tissue, the GM concentration was about 95.50 ±16.50 μg/ml and 80.20 ± 13.80 μg/ml from the plastic nano-HA/PHBV-PEG-GM-DDS on the 1st day, then decreased gradually. After 56 days of operation, the GM concentration still exceeded the minimum inhibitory concentration for the staphylococcus aureus, but the peak level of serum GM concentration was under the nephrotoxicity concentration. Conclusion Plastic nano-HA/PHBV-PEG-GM-DDS was a good drug delivery system with sustained antibiotic effect in vivo. It was an effective method for the treatment of osteomyelitis.