The Development of a Macromolecular Analgesic for Arthritic Pain
| Autor: | Laura Weber, Gang Zhao, Xin Wei, Xiaobei Wang, Dong Wang, Rongguo Ren, Huiling Pang, Hongjiang Yuan, Hanjun Wang, Junxiao Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
animal structures Polymers media_common.quotation_subject Analgesic Pharmaceutical Science Arthritis Pain 02 engineering and technology Pharmacology 030226 pharmacology & pharmacy Article Arthritis Rheumatoid 03 medical and health sciences Mice 0302 clinical medicine Phagocytosis Drug Discovery medicine Animals Hydromorphone Prodrugs Tissue Distribution Internalization media_common Acrylamides Analgesics Chemistry Prodrug 021001 nanoscience & nanotechnology medicine.disease Arthritis Experimental In vitro Endocytosis Rats Analgesics Opioid RAW 264.7 Cells Treatment Outcome Opioid Rats Inbred Lew Systemic administration Molecular Medicine 0210 nano-technology Tail flick test medicine.drug |
| Popis: | The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain. |
| Databáze: | OpenAIRE |
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