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Controlled release of clot-dissolving tissue-type plasminogen activator from a poly(L-glutamic acid)
1College of Pharmacy, The University of Michigan, 428 Church Street, 48109-1065, Ann Arbor, MI, USA
Abstract:
With the aim of developing an effective therapeutic modality for treatment of thrombosis, a tissue-type plasminogen activator (t-PA)-loaded porous poly(L-glutamic acid) (PLGA) semi-interpenetrating polymer network (semi-IPN) hydrogel was developed as a possible local drug delivery system. Porous structure of hydrogel was essential in this system to yield a large surface area so that t-PA release could be facilitated. This semi-IPN hydrogel was prepared using the method of free-radical polymerization and crosslinking of polyethylene glycol (PEG)-methacrylate through the PLGA network. Sodium bicarbonate (NaHCO(3)) was added to function as a foaming agent under acidic conditions, rendering the semi-IPN hydrogel to be porous. While the added NaHCO(3) provided gas foam in the reaction mixture, the pH in the hydrogel increased to about 7 to 8, which stimulated the polymerization. The porous structure that was presented at both the surface and sublayer was stabilized during hydrogel formation and freeze-drying. The hydrogel thus prepared possessed a porous structure of 10-20 microm in diameter, as determined by scanning electron microscopy. Results showed that the above hydrogel preparation process did not significantly alter the specific activity of the entrapped t-PA with regard to plasminogen activation and fibrin clot lysis ability. The t-PA release from this semi-IPN hydrogel was examined by measuring the plasmin activity using the chromogenic substrate S-2251. Findings in this paper demonstrated that the porous structure of the hydrogel facilitated t-PA release when compared to the dense structure. Aside from the porous structure, other factors including the content of the crosslinker, PLGA and t-PA could all be varied to regulate t-PA release from the hydrogel. These results suggest that a porous PLGA semi-IPN hydrogel could potentially be a useful local delivery system to release active t-PA primarily at the site of a thrombus.