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Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2018 Apr 28; Vol. 276, pp. 102-112. Date of Electronic Publication: 2018 Mar 07. - Publication Year :
- 2018
-
Abstract
- This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38α/β MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution. The PH-NPPs had a mean diameter of 14.2 μm and drug loading of ~31.5% (w/w), and ~20% of the PH was released over 3 months. The NPPs did not exhibit toxicity to cultured human OA synoviocytes at 100 × IC <subscript>50</subscript> . Finally, in vivo studies showed good retention of PH-NPPs in the joint and adjacent tissues for up to 2 months, and the PH-NPPs exhibited good functional relevance by significantly reducing inflammation and joint destruction and by inhibiting several biomarkers (e.g., IL-1β). In conclusion, local treatment with PH-NPPs, used as an extended-release drug delivery system, improved inflammation and joint degradation in two distinct mouse models, indicating treatment potential for human OA.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal chemistry
Benzamides chemistry
Delayed-Action Preparations administration & dosage
Delayed-Action Preparations chemistry
Disease Models, Animal
Drug Liberation
Humans
Male
Mice, Inbred C57BL
Nanoparticles chemistry
Protein Kinase Inhibitors chemistry
Pyridones chemistry
Anti-Inflammatory Agents, Non-Steroidal administration & dosage
Benzamides administration & dosage
Nanoparticles administration & dosage
Osteoarthritis drug therapy
Protein Kinase Inhibitors administration & dosage
Pyridones administration & dosage
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 276
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 29524442
- Full Text :
- https://doi.org/10.1016/j.jconrel.2018.03.007