Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis
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| Název: | Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis |
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| Autoři: | Maudens, Pierre Marc Xavier, Seemayer, Christian Alexander, Pfefferlé, François, Jordan, Olivier, Allémann, Eric |
| Zdroj: | Journal of Controlled Release, Vol. 276 (2018) pp. 102-112 |
| Informace o vydavateli: | Elsevier BV, 2018. |
| Rok vydání: | 2018 |
| Témata: | Male, 0301 basic medicine, Benzamides/administration & dosage/chemistry, Pyridones, p38 Mitogen-Activated Protein Kinases, 03 medical and health sciences, Osteoarthritis, Osteoarthritis/drug therapy, Animals, Humans, Protein Kinase Inhibitors/administration & dosage/chemistry, Protein Kinase Inhibitors, ddc:615, 0303 health sciences, Anti-Inflammatory Agents, Non-Steroidal, Pyridones/administration & dosage/chemistry, Mice, Inbred C57BL, Disease Models, Animal, Drug Liberation, Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/chemistry, Delayed-Action Preparations/administration & dosage/chemistry, Nanoparticles/administration & dosage/chemistry, Delayed-Action Preparations, Benzamides, Nanoparticles, p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors |
| Popis: | 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 × IC50. 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. |
| Druh dokumentu: | Article |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2018.03.007 |
| Přístupová URL adresa: | https://archive-ouverte.unige.ch/unige:141549/ATTACHMENT01 https://pubmed.ncbi.nlm.nih.gov/29524442 https://www.ncbi.nlm.nih.gov/pubmed/29524442 https://www.sciencedirect.com/science/article/pii/S0168365918301299 https://archive-ouverte.unige.ch/unige:141549 http://europepmc.org/abstract/MED/29524442 https://pubmed.ncbi.nlm.nih.gov/29524442/ https://archive-ouverte.unige.ch/unige:141549/ATTACHMENT01 https://archive-ouverte.unige.ch/unige:141549 https://archive-ouverte.unige.ch/unige:141549 https://doi.org/10.1016/j.jconrel.2018.03.007 |
| Rights: | Elsevier TDM CC BY NC ND |
| Přístupové číslo: | edsair.doi.dedup.....dd923cfc3df1e7e5e0b9a10c1e9b7bbf |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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 × IC50. 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. |
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| ISSN: | 01683659 |
| DOI: | 10.1016/j.jconrel.2018.03.007 |