title: Graphene oxide stabilized by PLA-PEG copolymers for the controlled delivery of paclitaxel.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacy, Medical School, University of Patras, 26 500 Patras, Greece.
authors: A
authors: A
authors: Angelopoulou
authors: Department of Pharmacy, Medical School, University of Patras, 26 500 Patras, Greece.
authors: E
authors: E
authors: Voulgari
authors: Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece.
authors: E K
authors: EK
authors: Diamanti
authors: Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece.
authors: D
authors: D
authors: Gournis
authors: Department of Pharmacy, Medical School, University of Patras, 26 500 Patras, Greece. Electronic address: avgoust@upatras.gr.
authors: K
authors: K
authors: Avgoustakis
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003102:Colloids; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004355:Drug Stability; D005240:Feasibility Studies; D005434:Flow Cytometry; D006108:Graphite / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008027:Light; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D053758:Nanoparticles; D010087:Oxides / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012542:Scattering, Radiation; D012965:Sodium Chloride / Q000737:chemistry; D012995:Solubility; D013010:Sonication; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003102:Colloids; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D010087:Oxides; D011091:Polyesters; D011092:Polyethylene Glycols; D012965:Sodium Chloride; C033616:poly(lactide); D006108:Graphite; D017239:Paclitaxel
keywords: Colloidal stability; Cytotoxicity; Graphene oxide; PLA–PEG; Paclitaxel