title: Methotrexate Locally Released from Poly(ε-Caprolactone) Implants: Inhibition of the Inflammatory Angiogenesis Response in a Murine Sponge Model and the Absence of Systemic Toxicity.
abstract: In this study, the methotrexate (MTX) was incorporated into the poly(ε-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4 days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-α and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile.
authors.affiliation: Center of Research in Biological Science, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Leandro Gonzaga
authors.initials: LG
authors.lastname: De Oliveira
authors.affiliation: Center of Research in Biological Science, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Letícia Aparecida
authors.initials: LA
authors.lastname: Figueiredo
authors.affiliation: Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Gabriella Maria
authors.initials: GM
authors.lastname: Fernandes-Cunha
authors.affiliation: Center of Research in Biological Science, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Marina Barcelos
authors.initials: MB
authors.lastname: De Miranda
authors.affiliation: Center of Research in Biological Science, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Laser Antônio
authors.initials: LA
authors.lastname: Machado
authors.affiliation: School of Pharmacy, Federal University of São João del-Rei, Divinópolis, Minas Gerais, Brazil.
authors.forename: Gisele Rodrigues
authors.initials: GR
authors.lastname: Da Silva
authors.affiliation: Center of Research in Biological Science, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Sandra Aparecida Lima
authors.initials: SA
authors.lastname: De Moura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D003094:Collagen / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D003692:Delayed-Action Preparations / Q000737:chemistry*; D016503:Drug Delivery Systems; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011091:Polyesters / Q000737:chemistry*; D019736:Prostheses and Implants
chemical_list: D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D011091:Polyesters; C016240:polycaprolactone; D003094:Collagen; D008727:Methotrexate
keywords: biodegradable polymers; biomaterials; controlled release; controlled release/delivery; drug delivery; polymer; polymeric drug carrier; polymeric drug delivery systems; targeted drug delivery; toxicology