title: Temperature-responsive polymeric nanospheres containing methotrexate and gold nanoparticles: A multi-drug system for theranostic in rheumatoid arthritis.
abstract: Inflammation plays a crucial role in rheumatoid arthritis progress. In the present work, a novel stealth polymeric nanospheres platform able to carry anti-inflammatory drugs and an imaging agent was developed. Incorporation of gold nanoparticles will allow photoacoustic imaging and near infra-red photothermal application. Through emulsion-diffusion evaporation technique methotrexate and gold nanoparticles were incorporated in the pegylated-poly(DL-lactic-co-glycolic acid) nanospheres. In vitro drug release assays revealed pH and temperature-dependence on gold nanoparticles. Blank nanospheres exhibited negligible in vitro cytotoxicity, while methotrexate-loaded nanospheres hampered monocytes and macrophages viability at a higher level than free methotrexate. Confocal fluorescent microscopy and flow cytometry revealed effective nanospheres internalization, and that their cellular uptake was energy dependent mediated by caveolae and clathrin-endocytosis mechanism. Finally, MTX-loaded multifunctional nanospheres containing gold lead to a significant reduction of IL-1β, IL-6 and TNF-α inflammatory cytokines produced by monocytes and macrophages upon in vitro inflammatory stimulation, suggesting a favorable anti-inflammatory activity. These results confirm that the multifunctional nanospheres represent a promising theranostic platform for RA diagnosis and intracellular treatment, by combining methotrexate and gold nanoparticles for a highly effective targeted chemo-photothermal therapy.
authors.affiliation: UCIBIO/REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: slima@ff.up.pt.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Costa Lima
authors.affiliation: UCIBIO/REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles; D008727:Methotrexate / Q000008:administration & dosage*; D054118:Nanospheres; D011108:Polymers / Q000737:chemistry*; D013696:Temperature; D000068936:Theranostic Nanomedicine
chemical_list: D011108:Polymers; D006046:Gold; D008727:Methotrexate
keywords: Cellular uptake; Controlled drug release; Gold nanoparticles; Temperature-responsiveness; in vitro anti-inflammatory activity