PMID- 24854983 OWN - NLM STAT- MEDLINE DCOM- 20150622 LR - 20191210 IS - 1530-8022 (Electronic) IS - 0885-3282 (Linking) VI - 29 IP - 4 DP - 2014 Oct TI - In vitro evaluation of effects of sustained anti-TNF release from MPEG-PCL-MPEG and PCL microspheres on human rheumatoid arthritis synoviocytes. PG - 524-42 LID - 10.1177/0885328214535958 [doi] AB - Anti-tumor necrosis factor alpha (TNFalpha) drugs such as etanercept (ETN) have been mostly used in systemic treatment of rheumatoid arthritis. To eliminate the side effects in long-term treatments and to achieve a local sustained anti-inflammatory effect, a controlled drug delivery system is needed for anti-TNFalpha drugs. This study aims to develop novel injectable microcarriers of ETN that can provide long-term controlled release of this protein drug upon intra-articular application. In this study, poly(epsilon-caprolactone) (PCL) and its copolymer with poly(ethylene glycol), methoxypoly(ethylene glycol)-poly(epsilon-caprolactone)-methoxypoly(ethylene glycol) microspheres (MPEG-PCL-MPEG) were compared for their prospective success in rheumatoid arthritis treatment. Microspheres with smooth surface of a mean particle diameter of approximately 5 mum were prepared with both polymers. MPEG-PCL-MPEG microspheres had higher encapsulation efficiency than PCL microspheres. The activity of encapsulated ETN within MPEG-PCL-MPEG microspheres also retained while 90% of the activity of ETN within PCL microspheres could retain during 90-day release. MPEG-PCL-MPEG microspheres showed faster ETN release compared to PCL microspheres in various release media. Cumulative amounts of ETN released from both types of microspheres were significantly lower in cell culture medium and in synovial fluids than in phosphate buffered saline. This was mainly due to protein adsorption onto microspheres. Hydrophilic MPEG segment enhanced ETN release while preventing protein adsorption on microspheres compared to PCL. Sustained ETN release from microspheres resulted with a significant decrease in pro-inflammatory cytokines (TNFalpha, IFNgamma, IL-6, IL-17) and MMP levels (MMP-3, MMP-13), while conserving viability of fibroblast-like synoviocytes compared to the free drug. Results suggest that MPEG-PCL-MPEG is a potential copolymer of PCL that can be used in development of biomedical materials for effective local treatment purposes in chronic inflammatory arthritis owing to enhanced hydrophilicity. Yet, PCL microspheres are also promising systems having good compatibility to synoviocytes and would be especially the choice for treatment approach requiring longer term and slower release. CI - (c) The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav. FAU - Erdemli, Ozge AU - Erdemli O AD - Department of Engineering Sciences, Middle East Technical University, Ankara, Turkey. FAU - Ozen, Seza AU - Ozen S AD - Department of Paediatric Rheumatology, Hacettepe University, Ankara, Turkey. FAU - Keskin, Dilek AU - Keskin D AD - Department of Engineering Sciences, Middle East Technical University, Ankara, Turkey Biomaterials and Tissue Engineering Center of Excellence, Middle East Technical University, Ankara, Turkey. FAU - Usanmaz, Ali AU - Usanmaz A AD - Department of Chemistry, Middle East Technical University, Turkey. FAU - Batu, Ezgi Deniz AU - Batu ED AD - Department of Paediatric Rheumatology, Hacettepe University, Ankara, Turkey. FAU - Atilla, Bulent AU - Atilla B AD - Department of Orthopedics and Traumatology, Hacettepe University, Turkey. FAU - Tezcaner, Aysen AU - Tezcaner A AD - Department of Engineering Sciences, Middle East Technical University, Ankara, Turkey Biomaterials and Tissue Engineering Center of Excellence, Middle East Technical University, Ankara, Turkey tezcaner@metu.edu.tr. LA - eng PT - Comparative Study PT - Evaluation Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140521 PL - England TA - J Biomater Appl JT - Journal of biomaterials applications JID - 8813912 RN - 0 (Biocompatible Materials) RN - 0 (Cytokines) RN - 0 (Delayed-Action Preparations) RN - 0 (Immunoglobulin G) RN - 0 (Inflammation Mediators) RN - 0 (Polyesters) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (methoxy poly(ethylene glycol)-poly(epsilon-caprolactone)-methoxy poly(ethylene glycol)) RN - 24980-41-4 (polycaprolactone) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - OP401G7OJC (Etanercept) SB - IM MH - Arthritis, Rheumatoid/*drug therapy/metabolism/pathology MH - Biocompatible Materials/*chemistry MH - Cell Survival/drug effects MH - Cells, Cultured MH - Cytokines/metabolism MH - Delayed-Action Preparations MH - *Drug Delivery Systems MH - Etanercept MH - Humans MH - Immunoglobulin G/*administration & dosage MH - In Vitro Techniques MH - Inflammation Mediators/metabolism MH - Injections, Intra-Articular MH - Materials Testing MH - Matrix Metalloproteinases/metabolism MH - Microspheres MH - Particle Size MH - Polyesters/chemistry MH - Polyethylene Glycols/chemistry MH - Receptors, Tumor Necrosis Factor/*administration & dosage MH - Synovial Membrane/drug effects/metabolism/pathology MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors OTO - NOTNLM OT - Etanercept OT - amphiphilic triblock copolymer OT - anti-tumor necrosis factor alpha drugs OT - intra-articular delivery OT - methoxy poly(ethylene glycol)-poly(epsilon-caprolactone)-methoxy poly(ethylene glycol) OT - microspheres OT - rheumatoid arthritis EDAT- 2014/05/24 06:00 MHDA- 2015/06/24 06:00 CRDT- 2014/05/24 06:00 PHST- 2014/05/24 06:00 [entrez] PHST- 2014/05/24 06:00 [pubmed] PHST- 2015/06/24 06:00 [medline] AID - 0885328214535958 [pii] AID - 10.1177/0885328214535958 [doi] PST - ppublish SO - J Biomater Appl. 2014 Oct;29(4):524-42. doi: 10.1177/0885328214535958. Epub 2014 May 21.