Žid Lukáš, Zeleňák Vladimír, Girman Vladimír, Bednarčík Jozef, Zeleňáková Adriana, Szűcsová Jaroslava, Hornebecq Virginie, Hudák Alexander, Šuleková Monika, Váhovská Lucia
Department of Inorganic Chemistry Faculty of Science, P. J. Šafárik University Moyzesova 11 SK-041 54 Košice Slovak Republic
Institute of Physics, P. J. Šafárik University Park Angelinum 9 04001 Košice Slovakia.
RSC Adv. 2020 Apr 21;10(27):15825-15835. doi: 10.1039/d0ra02091e.
In this work, we have prepared and investigated a redox-responsive drug delivery system (DDS) based on a porous carrier. Doxorubicin (DOX), a chemotherapy medication for treatment of different kinds of cancer, was used as a model drug in the study. DOX was loaded in ordered hexagonal mesoporous silica SBA-15, a nanoporous material with good biocompatibility, stability, large pore size and specific surface area ( = 908 m g, = 0.79 cm g, = 5.9 nm) and easy surface modification. To prepare the redox-responsive system, cystamine derivative ligands, with redox active disulphide linkers were grafted onto the surface of SBA-15. To ensure no significant premature release of DOX from the porous system, thioglycolic acid modified ZnS nanoparticles (ZnS-COOH NPs) were used as pore capping agents. The grafted redox-responsive cystamine derivative ligand containing disulphide linkers was bonded by a peptide bond to the thioglycolic acid groups of ZnS-COOH NPs, capping the pores. Once the disulphide bond was cleaved, the ZnS-COOH NPs caps were released and pores were opened to deliver the DOX cargo. The dithiol bond was cleavable by redox active molecules such as dithiothreitol (DTT) or glutathione, the concentration of which in cancer cells is 4 times higher than in healthy cells. The redox release of DOX was studied in two different media, physiological saline solution with DTT and saline without DTT. The prepared DDS proved the concept of redox responsive release. All samples were characterised by powder X-ray diffraction (XRD), transition electron microscopy (TEM), nitrogen adsorption/desorption at 77 K, Fourier-transform infrared spectroscopy (FTIR), thermal analysis and zeta potential measurements. The presence of semiconducting ZnS nanoparticle caps on the pore openings was detected by magnetic measurements using SQUID magnetometry showing that such cargo systems could be monitored using magnetic measurements which opens up the possibilities of using such drug delivery systems as theranostic agents.
在本研究中，我们制备并研究了一种基于多孔载体的氧化还原响应型药物递送系统（DDS）。阿霉素（DOX）作为一种用于治疗多种癌症的化疗药物，被用作本研究中的模型药物。DOX被负载于有序介孔二氧化硅SBA-15中，SBA-15是一种具有良好生物相容性、稳定性、较大孔径和比表面积（比表面积 = 908 m²/g，孔容 = 0.79 cm³/g，孔径 = 5.9 nm）且易于表面修饰的纳米多孔材料。为制备氧化还原响应系统，将具有氧化还原活性二硫键连接体的胱胺衍生物配体接枝到SBA-15表面。为确保DOX不会从多孔系统中显著过早释放，使用巯基乙酸修饰的硫化锌纳米颗粒（ZnS-COOH NPs）作为孔封端剂。含有二硫键连接体的接枝氧化还原响应胱胺衍生物配体通过肽键与ZnS-COOH NPs的巯基乙酸基团结合，从而封端孔道。一旦二硫键断裂，ZnS-COOH NPs封端剂被释放，孔道打开以释放DOX负载物。二硫醇键可被氧化还原活性分子如二硫苏糖醇（DTT）或谷胱甘肽裂解，癌细胞中这些分子的浓度比健康细胞高4倍。在两种不同介质中研究了DOX的氧化还原释放，即含有DTT的生理盐水溶液和不含DTT的生理盐水。所制备的DDS证实了氧化还原响应释放的概念。所有样品通过粉末X射线衍射（XRD）、透射电子显微镜（TEM）、77 K下的氮气吸附/脱附、傅里叶变换红外光谱（FTIR）、热分析和zeta电位测量进行表征。使用超导量子干涉仪磁强计通过磁性测量检测到孔口处存在半导体硫化锌纳米颗粒封端剂，表明这种负载系统可通过磁性测量进行监测，这为将这种药物递送系统用作诊疗试剂开辟了可能性。
