| Summary: | 碩士 === 長庚大學 === 基礎醫學研究所 === 94 === The use of recombinant tissue plasminogen activator (rt-PA) to cause thrombolysis has been an important development in the treatment of ischemic stroke. However, rt-PA exhibits potential to induce hemorrhage as its major side effect. Targeted delivery of thrombolytic agents to the site of thrombus may greatly reduce the side effect and amount of the drug used. In the current study, we developed a rat embolic model for evaluation of magnetic targeted delivery of thrombolytic agents. In anesthetized rats, a whole blood clot was injected from a retrograde catheter in the right iliac artery and lodged in the left iliac artery before branching into femoral and pudic epigastric arteries. The hemodynamic changes in response to clot lodging and thrombolysis were monitored with ultrasonic and laser Doppler flowmetry. Thirty min after intra-arterial infusion of recombinant tissue plasminogen activator (rt-PA) and human tissue urinary plasminogen activator (HTUPA) reversed approximately 69 and 62 % of the iliac blood flow and most of the skin perfusion of the left hind limb. Placement of an NdFeB magnet above the left iliac artery for 15 min caused intra-arterial retention of magnetic nanoparticle nanomag®-D (250 nm; 0.1 and 1 mg/kg) against hemodynamic dragging force in the presence and absence of the clot, as illustrated by histological staining with Prussian blue. Intra-arterial or intravenous injection of nanomag®-D, PPy, d-PPy, PAn, d-PAn or USPIO-102 (1 mg/kg) did not alter basal hemodynamics or hemodynamic responses to angiotensin II or acetylcholine. In addition, injection of nanomag®-D to the microcirculation of cremaster muscle of rat did not alter the blood flow. Intra-arterial injection of nanomag®-D, PPy, d-PPy, PAn or d-PAn did not cause retention in the renal tissues without magnetic field. Nevertheless, incubation of nanomag®-D (30-100 μg/ml), PAn and d-PAn (100-300 μg/ml) with cultured vascular smooth muscle cells for 2-6 days did suppress cell proliferation. In conclusion, we have demonstrated a rat embolic model that can be used for acute magnetic targeted delivery of thrmobolytic drugs; however, potential long term toxicity of these nanoparticles can not be ignored.
|
|---|
