Controlled release of clot-dissolving tissue-type plasminogen activator from a poly(L-glutamic acid) semi-interpenetrating polymer network hydrogel

With the aim of developing an effective therapeutic modality for treatment of thrombosis, a tissue-type plasminogen activator (t-PA)-loaded porous pol y(L-glutamic acid) (PLGA) semi-interpenetrating polymer network (semi-IPN) hydrogel was developed as a possible local drug delivery system. Porous str ucture of hydrogel was essential in this system to yield a large surface ar ea so that t-PA release could be facilitated. This semi-IPN hydrogel was pr epared using the method of free-radical polymerization and crosslinking of polyethylene glycol (PEG)-methacrylate through the PLGA network. Sodium bic arbonate (NaHCO3) was added to function as a foaming agent under acidic con ditions, rendering the semi-IPN hydrogel to be porous. While the added NaHC O3 provided gas foam in the reaction mixture, the pH in the hydrogel increa sed to about 7 to 8, which stimulated the polymerization. The porous struct ure that was presented at both the surface and sublayer was stabilized duri ng hydrogel formation and freeze-drying. The hydrogel thus prepared possess ed a porous structure of 10-20 mum in diameter, as determined by scanning e lectron microscopy. Results showed that the above hydrogel preparation proc ess 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 plasm in activity using the chromogenic substrate S-2251. Findings in this paper demonstrated that the porous structure of the hydrogel facilitated t-PA rel ease when compared to the dense structure. Aside from the porous structure, other factors including the content of the crosslinker, PLGA and t-PA coul d 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 thr ombus. (C) 2001 Elsevier Science BY All rights reserved.