A combined therapy of rtPA-loaded thermoresponsive gels and ultrasound on hematoma in a rat model of intracerebral hemorrhage

Abstract

To develop and validate an effective method for the removal of residual intracerebral hematoma, we prepared a recombinant tissue-type plasminogen activator (rtPA)-loaded Pluronic F127 (NP-rtPA) delivery system, assess the use of ultrasound (US) to dissolve hematoma in vitro and in a rat model of intracerebral hemorrhage (ICH) in vivo, and evaluate the neurological response of the ICH rat model. There were five experimental groups: control, rtPA, rtPA + US, NP-rtPA and NP-rtPA + US, and the US treatment was at 1 MHz, 0.4 W. The hematoma dissolution in vitro was measured at 6, 24, and 72 hours. Then, to create a rat model of ICH in vivo, rtPA and NP-rtPA were injected into the hematoma cavity with ultrasound-controlled release of rtPA at scheduled times. The neurological behavior of rats was evaluated. NP-rtPA + US dissolved hematoma 40% at 6 hours and 60% at 72 hours compared with the control rtPA (dissolving 20% and 40%, respectively). There was an obvious difference at 0 and 1 day between the rtPA and Np-rtPA. The water content in brain tissue was found to be statistically different. Differences in the behavior of rats treated with rtPA + US and Np-rtPA + US were statistically significant at 21 and 28 days. Ultrasound can control the release of rtPA from rtPA-Pluronic F127, making it better at dissolving hematoma, this effect was better than that achieved with common rtPA. In addition, this treatment may reduce brain edema and provide an effective method for the removal of residual hematoma in ICH using minimally invasive surgery.