Sustained release of matrix metalloproteinase-3 to trabecular meshwork cells using biodegradable PLGA microparticles.

Accumulation of extracellular matrix (ECM) materials in the trabecular meshwork (TM) is believed to be a contributing factor to intraocular pressure (IOP) elevation, a risk factor/cause of primary open angle glaucoma, a major blinding disease. Matrix metalloproteinase-3 (MMP-3) is one of the proteinases that can effectively degrade ECM elements such as fibronectin, and MMP-3 delivery to the TM represents a promising approach for IOP reduction and treatment of glaucoma. In this study, we tested the feasibility of using polymeric microparticles to achieve a slow and sustained release of active MMP-3 to cultured human TM cells. ß-Casein, with molecular weight (24 kDa) and hydrophobicity similar to those of the active MMP-3 fragment (19.2 kDa), was first employed as a model for initial testing. ß-casein was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microparticles using a double emulsion procedure at an encapsulation efficiency of approximately 45%. The PLGA microparticles were chosen given their biocompatibility and the proven capacity of sustained release of encapsulated molecules. The release test conducted in the culture medium showed a slow and sustained release of the protein over 20 days without a significant initial burst release. Active MMP-3 was subsequently encapsulated into PLGA microparticles with an encapsulation efficiency of approximately 50%. A biofunctional assay utilizing human TM cells was set up in which the reduction of fibronectin was used as an indicator of enzyme activity. It was observed that fibronectin staining was markedly reduced by the medium collected from MMP-3-microparticle-treated cultures compared to that from blank- and ß-casein-microparticle controls, which was validated using a direct MMP-3 activity assay. The controlled release of MMP-3 from the microparticles resulted in sustained degradation of fibronectin up to 10 days. This proof-of-concept undertaking represents the first study on the controlled and sustained release of active MMP-3 to TM cells via encapsulation into PLGA microparticles as a potential treatment of glaucoma.

Risk of coronary artery stenosis in Iranian type 2 diabetics: is there a role for matrix metalloproteinase-3 gene (-1612 5A/6A) polymorphism?

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To investigate the association of matrix metalloproteinase-3 (MMP-3) polymorphism with susceptibility to coronary artery stenosis (CAS) and the number of diseased vessels in patients withtype 2 diabetes mellitus (T2DM).MethodsThe study population comprised 618 unrelated Iranian individual subjects, including 305 angiographically documented CAS patients with T2DM and 313 control subjects with T2DM. MMP3genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism.ResultsSignificant differences between cases and controls were observed for MMP3 genotype frequencies (p < 0.01). The 6A allele was high frequently seen in the disease group, compared with the control group (64.75 vs. 56.24%, 6A/6A + 5A/6A vs. 5A/5A, p < 0.05). The association of this polymorphism with the severity of stenosis were also evaluated which according to results distribution of MMP3genotypes were not significantly different as compared with the severity of stenosis (p > 0.05).ConclusionsFrequency of the 6A allele of the human MMP3 gene is an independent risk factor for CAS in the Iranian T2DM studied (AU)