Liu Wei, Zhang Xuejin, Wang Rui, Xu Hong, Chi Bo
a State Key Laboratory of Materials-Oriented Chemical Engineering , Nanjing Tech University , Nanjing , China.
b Biopolymer Materials Laboratory, Department of Light Industry , Nanjing Tech University , Nanjing , China.
J Biomater Sci Polym Ed. 2016;27(6):490-504. doi: 10.1080/09205063.2016.1140612.
Much attention has been given to the problem of drug delivery through the cell membrane in order to treat and manage bone diseases recently. The aim of this study was to develop nanoparticles made of amino- and histidinyl-modified amphiphilic β-cyclodextrins (β-CDs) entrapping osteoclast inhibitor, a hydrophobic oligopeptides drug, across the membrane of bone marrow-derived macrophages (BMMs). Drug-loaded β-CDs nanoparticles (NPs) were prepared by the emulsion solvent evaporation technique and fully characterized for size, zeta potential, and entrapment efficiency. Spherical NPs displaying a hydrodynamic radius of about 295 nm which did not change upon storage as an aqueous dispersion, a positive zeta potential, and entrapment efficiency of drug very close to 98% were produced. Flow cytometry and spectrofluorimetry analysis indicated that the model drug itself was not taken up by the BMMs; however, NP systems underwent significant cellular uptake. In particular, histidinyl group-modified CD (β-CD-H) NPs were taken up more efficiently than amino group-modified (β-CD-A) ones. Cellular uptake mechanism study demonstrated that the permeability of drug-loaded NPs across the membrane of BMMs is probably due to macropinocytosis pathway. Cell viability studies showed that both β-CD-A and β-CD-H exhibited no significant cytotoxicity up to 1.0 mg/ml against the cells. These results highlight the developed β-CD-H NPs have great potential in safely and effectively delivering osteoclast inhibitors and other therapeutic agents toward bone disease.
为了治疗和管理骨疾病，近年来人们对药物通过细胞膜的递送问题给予了极大关注。本研究的目的是开发由氨基和组氨酸修饰的两亲性β-环糊精（β-CD）制成的纳米颗粒，其包裹破骨细胞抑制剂（一种疏水性寡肽药物），并使其穿过骨髓来源巨噬细胞（BMM）的膜。通过乳液溶剂蒸发技术制备了载药β-CD纳米颗粒（NPs），并对其尺寸、zeta电位和包封率进行了全面表征。制备出的球形NPs的流体动力学半径约为295nm，作为水分散体储存时其大小不变，具有正的zeta电位，药物包封率非常接近98%。流式细胞术和荧光光谱分析表明，模型药物本身未被BMM摄取；然而，NP系统发生了显著的细胞摄取。特别是，组氨酸修饰的CD（β-CD-H）NPs比氨基修饰的（β-CD-A）NPs摄取效率更高。细胞摄取机制研究表明，载药NPs穿过BMM膜的通透性可能归因于巨胞饮途径。细胞活力研究表明，β-CD-A和β-CD-H在浓度高达1.0mg/ml时对细胞均无显著细胞毒性。这些结果表明，所开发的β-CD-H NPs在安全有效地向骨疾病递送破骨细胞抑制剂和其他治疗剂方面具有巨大潜力。
