Angelopoulou A, Voulgari E, Diamanti E K, Gournis D, Avgoustakis K
Department of Pharmacy, Medical School, University of Patras, 26 500 Patras, Greece.
Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece.
Eur J Pharm Biopharm. 2015 Jun;93:18-26. doi: 10.1016/j.ejpb.2015.03.022. Epub 2015 Mar 24.
To investigate the application of water-dispersible poly(lactide)-poly(ethylene glycol) (PLA-PEG) copolymers for the stabilization of graphene oxide (GO) aqueous dispersions and the feasibility of using the PLA-PEG stabilized GO as a delivery system for the potent anticancer agent paclitaxel.
A modified Staudenmaier method was applied to synthesize graphene oxide (GO). Diblock PLA-PEG copolymers were synthesized by ring-opening polymerization of dl-lactide in the presence of monomethoxy-poly(ethylene glycol) (mPEG). Probe sonication in the presence of PLA-PEG copolymers was applied in order to reduce the hydrodynamic diameter of GO to the nano-size range according to dynamic light scattering (DLS) and obtain nano-graphene oxide (NGO) composites with PLA-PEG. The composites were characterized by atomic force microscopy (AFM), thermogravimetric analysis (TGA), and DLS. The colloidal stability of the composites was evaluated by recording the size of the composite particles with time and the resistance of composites to aggregation induced by increasing concentrations of NaCl. The composites were loaded with paclitaxel and the in vitro release profile was determined. The cytotoxicity of composites against A549 human lung cancer cells in culture was evaluated by flow cytometry. The uptake of FITC-labeled NGO/PLA-PEG by A549 cells was also estimated with flow cytometry and visualized with fluorescence microscopy.
The average hydrodynamic diameter of NGO/PLA-PEG according to DLS ranged between 455 and 534 nm, depending on the molecular weight and proportion of PLA-PEG in the composites. NGO/PLA-PEG exhibited high colloidal stability on storage and in the presence of high concentrations of NaCl (far exceeding physiological concentrations). Paclitaxel was effectively loaded in the composites and released by a highly sustained fashion. Drug release could be regulated by the molecular weight of the PLA-PEG copolymer and its proportion in the composite. The paclitaxel-loaded composites exhibited cytotoxicity against A549 cancer cells which increased with incubation time, in conjunction with the increasing with time uptake of composites by the cancer cells.
Graphene oxide aqueous dispersions were effectively stabilized by water-dispersible, biocompatible and biodegradable PLA-PEG copolymers. The graphene oxide/PLA-PEG composites exhibited satisfactory paclitaxel loading capacity and sustained in vitro drug release. The paclitaxel-loaded composites could enter the A549 cancer cells and exert cytotoxicity. The results justify further investigation of the suitability of PLA-PEG stabilized graphene oxide for the controlled delivery of paclitaxel.
研究水分散性聚（丙交酯）-聚（乙二醇）（PLA-PEG）共聚物在氧化石墨烯（GO）水分散体稳定化中的应用，以及使用PLA-PEG稳定的GO作为强效抗癌药物紫杉醇递送系统的可行性。
采用改良的施陶登迈尔法合成氧化石墨烯（GO）。在单甲氧基聚（乙二醇）（mPEG）存在下，通过丙交酯的开环聚合反应合成二嵌段PLA-PEG共聚物。根据动态光散射（DLS），在PLA-PEG共聚物存在下进行探针超声处理，以将GO的流体动力学直径减小到纳米尺寸范围，并获得具有PLA-PEG的纳米氧化石墨烯（NGO）复合材料。通过原子力显微镜（AFM）、热重分析（TGA）和DLS对复合材料进行表征。通过记录复合颗粒尺寸随时间的变化以及复合材料对NaCl浓度增加引起的聚集的抗性，评估复合材料的胶体稳定性。将复合材料负载紫杉醇，并测定其体外释放曲线。通过流式细胞术评估复合材料对培养的A549人肺癌细胞的细胞毒性。还用流式细胞术估计A549细胞对FITC标记的NGO/PLA-PEG的摄取，并通过荧光显微镜观察。
根据DLS，NGO/PLA-PEG的平均流体动力学直径在455至534nm之间，这取决于复合材料中PLA-PEG的分子量和比例。NGO/PLA-PEG在储存时以及在高浓度NaCl（远超过生理浓度）存在下表现出高胶体稳定性。紫杉醇有效地负载在复合材料中，并以高度持续的方式释放。药物释放可通过PLA-PEG共聚物的分子量及其在复合材料中的比例来调节。负载紫杉醇的复合材料对A549癌细胞表现出细胞毒性，其随孵育时间增加，同时癌细胞对复合材料的摄取也随时间增加。
水分散性、生物相容性和可生物降解的PLA-PEG共聚物有效地稳定了氧化石墨烯水分散体。氧化石墨烯/PLA-PEG复合材料表现出令人满意的紫杉醇负载能力和持续的体外药物释放。负载紫杉醇的复合材料可以进入A549癌细胞并发挥细胞毒性。这些结果证明有必要进一步研究PLA-PEG稳定的氧化石墨烯用于紫杉醇控释的适用性。
