Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain; Institute Lavoisier, CNRS UMR 8180, Université de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France.
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain.
Eur J Pharm Biopharm. 2018 Nov;132:11-18. doi: 10.1016/j.ejpb.2018.08.013. Epub 2018 Sep 1.
Due to their high porosity and versatile composition and structure, nanoscaled Metal-Organic Frameworks (nanoMOFs) have been recently proposed as novel drug delivery systems, and have been demonstrated to have important capacities and potential for controlled release of different active ingredients. Gentamicin (GM; a broad spectrum aminoglycoside antibiotic indicated in bacterial septicemia therapy) has great therapeutic interest, but the associated bioavailability and toxicity drawbacks accompanying high doses and repeated administration of this free drug make its encapsulation inside new nanocarriers necessary. GM encapsulation within two different porous biofriendly Fe and Zr-carboxylates nanoMOFs was performed by a simple impregnation method, with full characterization of the resulting GM-containing solid using a large panel of techniques (X ray powder diffraction-XRPD, Fourier transform infrared spectroscopy-FTIR, thermogravimetric analysis-TGA, N sorption, scanning electron microscopy-SEM, dynamic light scattering-DLS, ζ-potential, fluorescence spectroscopy and molecular simulations). High reproducible encapsulation rates, reaching 600 µg of GM per·mg of formulation, were obtained using the biocompatible mesoporous iron(III) trimesate nanoparticles (NPs) MIL-100(Fe) (MIL: Materials from Institut Lavoisier). In vitro GM delivery studies were also carried out using different oral and intravenous simulated physiological conditions, with complete antibiotic release within 8 h when using protein free media, but lower release rates in the presence of proteins. Furthermore, in vitro toxicity of GM-containing MIL-100(Fe) NPs was investigated on two different cell lines: a monocyte from leukemia (THP-1) and adherent fibroblastoid cells (NIH/3T3). These nanoMOFs had a low cytotoxic profile with IC values up to 1 mg·mL, ensuring adequate cell proliferation after 24 h. Finally, antibacterial activity studies were carried out on two Gram-positive bacteria and one Gram-negative bacterium: S. aureus, S. epidermidis and P. aeruginosa, respectively. GM-loaded MIL-100(Fe) NPs exhibited the same activity as free GM, confirming that the antibiotic activity of the released GM was conserved.
由于其高孔隙率以及多样的组成和结构，纳米尺度的金属-有机骨架（nanoMOFs）最近被提议作为新型药物输送系统，并且已经证明其具有控制不同活性成分释放的重要能力和潜力。庆大霉素（GM；一种广谱氨基糖苷类抗生素，用于治疗细菌性败血症）具有很大的治疗意义，但由于高剂量和重复给药会伴随生物利用度和毒性方面的缺点，因此需要将其封装在新的纳米载体中。通过简单的浸渍法将 GM 封装在两种不同的多孔生物友好型铁和锆羧酸 nanoMOFs 中，使用大量技术对所得含 GM 的固体进行了全面表征（X 射线粉末衍射-XRPD、傅里叶变换红外光谱-FTIR、热重分析-TGA、N 吸附、扫描电子显微镜-SEM、动态光散射-DLS、ζ-电位、荧光光谱和分子模拟）。使用生物相容性介孔三羧酸铁（III）纳米颗粒（NPs）MIL-100(Fe)（MIL：来自 Institut Lavoisier 的材料）可获得高重复性的封装率，达到 600µg GM 每毫克制剂。还进行了不同口服和静脉内模拟生理条件下的 GM 递送研究，在使用无蛋白介质时，抗生素在 8 小时内完全释放，但在存在蛋白质时释放率较低。此外，还研究了含有 GM 的 MIL-100(Fe) NPs 在两种不同细胞系上的体外毒性：白血病单核细胞（THP-1）和贴壁成纤维细胞（NIH/3T3）。这些 nanoMOFs 的细胞毒性较低，IC 值高达 1mg·mL，在 24 小时后确保细胞有足够的增殖。最后，对两种革兰氏阳性菌和一种革兰氏阴性菌进行了抗菌活性研究：金黄色葡萄球菌、表皮葡萄球菌和铜绿假单胞菌。负载 GM 的 MIL-100(Fe) NPs 表现出与游离 GM 相同的活性，证实了释放的 GM 的抗生素活性得以保留。
