针对骨肿瘤的二级靶向盐酸米托蒽醌纳米粒的制备及体内外性质评价

Preparation and characterization of dual-targeting nanostructure lipid carriers loading mitoxantrone hydrochloride for bone tumor

薄膜分散法制备了阿伦磷酸(ALN)配基和叶酸(FOL)配基共同修饰的二级靶向盐酸米托蒽醌(MTO)纳米粒(ALN-FOL-MTO-NLCs)。ALN-FOL-MTO-NLCs经原子力显微镜观察呈较规则类球体,平均粒径为(45.9±2.7)nm,Zeta电位为-(16.78±2.17)mV,包封率为(99.7±0.1)%。体外研究中ALN-FOL-MTO-NLCs显示出良好的骨盐吸附能力和K562细胞主动靶向能力,1 h内72.4%的纳米粒能吸附于羟基磷灰石,其K562细胞摄取量是普通纳米粒(MTO-NLCs)的3.19倍。高效液相色谱法研究了ALN-FOL-MTO-NLCs大鼠体内药代动力学及小鼠体内组织分布行为,其大鼠血浆AUC分别为MTO-NLCs和药物水溶液(MTO-INJ)的5.0和63.1倍,小鼠股骨AUC是叶酸单靶向制剂(FOL-MTO-NLCs)和药物水溶液(MTO-INJ)的3.7和5.0倍,且与FOL-MTO-NLCs相比,有效降低了药物在肝、脾、心、肾的分布,进一步降低了药物毒性。因此,与MTO-INJ和MTO-NLCs相比,ALN-FOL-MTO-NLCs具备良好的长循环效果,靶向骨组织的能力增加,且具备良好的肿瘤细胞靶向能力。

Dual-targeting nanostructure lipid carriers loading mitoxantrone hydrochloride（ALN-FOL-MTO-NLCs） were prepared by solvent evaporation.ALN-FOL-MTO-NLCs was quasi-spherical shapes observed by AFM and the mean particle size,Zeta potential and entrapment efficiency were（45.9±2.7） nm,-（16.78±2.17） mV and（99.7±0.1） %,respectively.In in vitro studies,ALN-FOL-MTO-NLCs showed good binding ability to hydroxyapatite,a model component of bone minerals,whereas unmodified NLCs yielded only nonspecific binding.The cellular uptake efficiency of ALN-FOL-NLCs were 3.19 times more than that of unmodified NLCs.The pharmacokinetics in rats and biodistribution in mice of NLCs loading MTO after intravenous injection were investigated by HPLC.The AUC of the blood PK profile of the drug formulated in ALN-FOL-MTO-NLCs were 5.0 and 63.1 times that of unmodified NLCs and free drug（MTO-INJ）,respectively.The AUC of the bone PK profile of the drug formulated in ALN-FOL-MTO-NLCs was 3.7-fold and 5.0-fold higher than that of FOL-MTO-NLCs and MTO-INJ,respectively.Compared with FOL-MTO-NLCs,ALN-FOL-MTO-NLCs displayed a reduction in drug toxicity because of the reduced accumulation in liver,spleen,heart and kidney.In turn,this allows administration of larger and more efficacious drug doses.In conclusion,compared with MTO-INJ and MTO-NLCs,ALN-FOL-MTO-NLCs displayed longer circulating capability,better bone targeting ability and tumor cells targeting efficiency.