The effect of a hydroxamic acid-containing polymer on active matrix metalloproteinases.
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.
Skarja
Gary A
GA
Rimon Therapeutics Ltd, 203 College St., Suite 403, Toronto, Ontario M5T1P9, Canada. skarja@rimontherapeutics.com
Brown
Allison L
AL
Ho
Rebecca K
RK
May
Michael H
MH
Sefton
Michael V
MV
D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008863:Microspheres; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*
D001672:Biocompatible Materials; D006877:Hydroxamic Acids; D011108:Polymers; D020782:Matrix Metalloproteinases