Synthesis of novel quaternary silica hybrid bioactive microspheres.

PURPOSE: To survey the preparation of novel hybrid microspheres of quaternary silicate glassy composition (SiO2 P2 O5 CaONa2 O) and the prospect of using them as an osteogenic system with enhanced bioactive properties for the development of hydroxyapatite. METHOD: In line with our previous synthetic procedure a two-step process was followed, wherein polystyrene (PS) microspheres were prepared by the emulsifier free-emulsion polymerization method and constituted the core for the sol-gel coating of the silicate inorganic shell. The development of the hybrid microspheres was based on silane and phosphate precursors and was assesses at different ratio of ethanol/water (of 9/1, 4/1, and 2/1, in mL) and at varied ammonia concentration of 4.8-1.0 mL. RESULTS: The hybrid microspheres had an average size ranged between 350 and 550 nm according to SEM, depending on the ethanol/water solution rate and ammonia content. The final microspheres probably exhibited a porous-like structure through the formation of diffused voids along with the low carbon content of the EDX analysis, which could be regulated by the catalyst content. The hybrid microspheres exhibited effective in vitro bioactivity assessed in simulated body fluids (SBF). CONCLUSION: Quaternary hybrid silica microspheres were effectively synthesized. The bioassay evaluation of the final microspheres revealed the rapid in vitro formation of a bone-like apatite layer. The results verify the bioactivity of the microspheres and promote further research of their suitability on regenerative treatment of bone abnormalities. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 112-120, 2018.

A new approach to fabricate bioactive silica binary and ternary hybrid microspheres.

Bioactive microspheres represent an extremely developing field in biomedical applications, such as bone tissue engineering and bone pathologies (metabolic bone disease, trauma or bone cancer). Their innate osteogenic properties have turned them to biomaterials with improved added value. The aim of this study was to prepare binary and ternary hybrid silica microspheres with enhanced bioactive properties according to our previous synthetic procedure. In brief, the synthetic approach based on the emulsifier free-emulsion polymerization method, by which polystyrene (PS) microspheres were produced and used as core template for the sol-gel coating method. During the coating reaction an inorganic shell was fabricated by silane and phosphate precursors (tetraethoxysilane, trimethylphosphate). The final microspheres were treated by different catalyst concentrations, during the coating process, which resulted in the formation of diffused voids (a porous-like structure). The in vitro bioactivity of the resultant microspheres was studied by treatment in simulated body fluids (SBF). The bioassay evaluation indicates the deposition of a bone-like apatite layer on microspheres' surface with enhanced bioresorbability, which verifies their bioactivity and permits their application in the treatment of bone pathologies.

Graphene oxide stabilized by PLA-PEG copolymers for the controlled delivery of paclitaxel.

PURPOSE: 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. CONCLUSION: 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.

A new approach for the one-step synthesis of bioactive PS vs. PMMA silica hybrid microspheres as potential drug delivery systems.

In this work, hybrid microspheres were prepared in a two-step process combining the emulsifier free-emulsion polymerization and the sol-gel coating method. In the first step, polystyrene (St) and poly(methyl methacrylate) (PMMA) microspheres were prepared as sacrificial template and in the second step a silanol shell was fabricated. The functionalized surface of the hybrid microspheres by silane analogs (APTES, TEOS) resulted in enhanced effects. The hollow microspheres were resulted either in an additional step by template dissolution and/or during the coating process. The microspheres' surface interactions and the size distribution were optimized by treatment in simulated body fluids, which resulted in the in vitro prediction of bioactivity. The bioassay test indicated that the induced hydroxyapatite resembled in structure to naturally occurring bone apatite. The drug doxorubicin (DOX) was used as a model entity for the evaluation of drug loading and release. The drug release study was performed in two different pH conditions, at acidic (pH=4.5) close to cancer cell environment and at slightly basic pH (pH=7.4) resembling the orthopedic environment. The results of the present study indicated promising hybrid microspheres for the potential application as drug delivery vehicles, for dual orthopedic functionalities in bone defects, bone inflammation, bone cancer and bone repair.

Raltitrexed (tomudex) administration in patients failing multiple prior chemotherapy regimens in advanced colorectal cancer: a pilot study.

PURPOSE: To evaluate efficacy of Raltitrexed, a specific thymidilate synthase inhibitor, in patients with advanced colorectal cancer (ACC) failing multiple prior chemotherapy regimens (e.g. 5-FU+LV, CPT-11, etc). METHODS: 20 patients with ACC; 13 males/7 females, median age 64 (range: 53-69), median Karnovsky PS: 80 (70-90), and sites of metastases; liver: 16, lung: 6, lymph nodes: 9, peritoneal: 8 and a life expectancy of at least 3 months, were entered in the present pilot study of Raltitrexed administration. All patients had progressed after prior chemotherapy with 5-FU+LV and subsequently CPT-11, and some had received further infusional 5-FU, Raltitrexed was administered at a dose of 3 mg/m2 i.v. every 21 days. RESULTS: 3 patients obtained stable disease (SID), 15%, with tumor marker decline (CEA, CA-19.9). Time-to-progression was 4.8 months (2.2-7) and survival 7.4 months (6.0-7.8). Toxicity was in general not severe and consisted mainly of myelosuppression; neutropenia (WHO) grade 2: 45% and grade 3: 22%, and anemia grade 1-2: 40%. CONCLUSION: Response to treatment with Raltitrexed is limited in patients with ACC failing multiple prior chemotherapy regimens, however, a limited percentage of patients with SD derived clinical benefit.