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

Sanja Turturro, Suhair Sunoqrot, Hongyu Ying, Seungpyo Hong, Beatrice Y.J.T. Yue

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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. β-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. β-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 β-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.

Original languageEnglish
Pages (from-to)3023-3032
Number of pages10
JournalMolecular Pharmaceutics
Volume10
Issue number8
DOIs
Publication statusPublished - 2013 Aug 5

Fingerprint

Trabecular Meshwork
Matrix Metalloproteinase 3
Fibronectins
Caseins
Intraocular Pressure
Glaucoma
Extracellular Matrix
polylactic acid-polyglycolic acid copolymer
Emulsions
Hydrophobic and Hydrophilic Interactions
Culture Media
Peptide Hydrolases
Molecular Weight
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Turturro, Sanja ; Sunoqrot, Suhair ; Ying, Hongyu ; Hong, Seungpyo ; Yue, Beatrice Y.J.T. / Sustained release of matrix metalloproteinase-3 to trabecular meshwork cells using biodegradable PLGA microparticles. In: Molecular Pharmaceutics. 2013 ; Vol. 10, No. 8. pp. 3023-3032.
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abstract = "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. β-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. β-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 β-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.",
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Sustained release of matrix metalloproteinase-3 to trabecular meshwork cells using biodegradable PLGA microparticles. / Turturro, Sanja; Sunoqrot, Suhair; Ying, Hongyu; Hong, Seungpyo; Yue, Beatrice Y.J.T.

In: Molecular Pharmaceutics, Vol. 10, No. 8, 05.08.2013, p. 3023-3032.

Research output: Contribution to journalArticle

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