The effect of a hydroxamic acid-containing polymer on active matrix metalloproteinases |
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| Authors: | Gary A Skarja Allison L Brown Rebecca K Ho Michael H May Michael V Sefton |
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| Institution: | 1. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China;2. Department of Restorative Dentistry, Hangzhou Dental Hospital, College of Stomatology, Zhejiang Chinese Medical University, Hangzhou, PR China;1. Georgia Regents University, Augusta, GA, USA;2. University of Utah, Salt Lake City, UT, USA;3. Western University of Health Sciences, Pomona, CA, USA;1. Department of Postgraduate Program in Dentistry, CEUMA University, São Luis, MA, Brazil;2. Dentistry Academic Unit, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile;3. Institute for Research in Dental Sciences, Faculty of Odontology, University of Chile, Chile;4. Department of Dentistry, University Center of Triangulo, Uberlandia, Brazil;5. Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil;6. School of Dentistry, Federal University of Ceará, Fortaleza, CE, Brazil;7. Biomaterials Department, King''s College London Dental Institute, London, UK;8. Department of Operative Dentistry and Endodontology, University of Marburg, Marburg, Germany;9. Department of Restorative Dentistry, School of Dentistry, State University of Ponta Grossa, PR, Brazil;1. Department of Orthodontics and Pediatric Dentistry, Araraquara School of Dentistry, UNESP – Univ Estadual Paulista, Araraquara, São Paulo, Brazil;2. Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, GA, USA;3. Department of Biomedicine, Unit of Dental Sciences and Biomaterials, University of Trieste, Trieste, Friuli Venezia Giulia, Italy;4. Department of Physiology and Pathology, Araraquara School of Dentistry, UNESP – Univ Estadual Paulista, Araraquara, São Paulo, Brazil |
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| Abstract: | Matrix metalloproteinase (MMP) sequestering polymer microspheres were prepared by a post-polymerization hydroxamic acid derivatization of poly(methyl methacrylate-co-methacrylic acid). The microspheres were designed to selectively bind MMPs from solutions on contact through a direct interaction between the polymer-bound hydroxamic acid groups and the characteristic catalytic site zinc atom common to all MMPs. MMP activity assays showed that the hydroxamic acid microspheres reduce MMP activity on contact in a time and concentration-dependent fashion. This effect was observed for several MMP subclasses (MMP-2, -3, -8 and -13) suggesting that the microspheres possess a broad-spectrum MMP binding capacity. However, inactive pro-forms of MMPs showed little binding affinity for the microspheres indicating that the interaction was dependent on MMP activation. The preferential binding of active MMPs was confirmed by MMP-3 and MMP-8 activation studies, which demonstrated significant increases in microsphere binding on activation. The MMP sequestering effect of the microspheres was also demonstrated in a physiologically relevant solution (human chronic wound fluid extract) indicating that the binding interaction was effective in a multi-component, competitive adsorption environment. Thus, the hydroxamic acid-containing microspheres may find use as localized, broad-spectrum MMP inhibitors for the treatment of a number of disease conditions characterized by elevated MMP activity. |
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