| Abstrakt: |
The use of erythrocyte entrapment as a strategy to deliver and protect exogenously administered enzymes for replacement therapy in selected genetic diseases has been evaluated in a mammalian model system. The uptake, tissue distribution, intracellular localization, andin vivolifetime of erythrocyteentrapped bovine glucuronidase were determined by a selective thermal inactivation assay after intravenous administration into glucuronidasedeficient mice. The exogenous activity was cleared from the circulation with a halflife of about 20 min and was no longer detectable at 2 hr. A concomitant uptake of the injected enzyme was observed in murine tissues, primarily the liver approximately 30 of the bovine activity was recovered at 30 min and maximal hepatic uptake, 71 of dose, was detected at 2 hr. Hepatic recovery of the bovine activity was observed to decrease in a biphasic pattern to nondetectable levels by 5 days. The recovery of the entrapped activity was characterized by a latency of detection in hepatic tissue up to 13 hr postinjection. At each time point more than 80 84100 of the recovered bovine activity was detected in the lysosomally enriched hepatic subcellular fraction. Maximal recoveries of 10 and 15 of administered dose were observed in splenic and renal tissues, respectively, soon after enzyme administration. In comparison to results obtained after intravenous administration of unentrapped bovine glucuronidase, erythrocyteentrapped activity was retained fourfold longer in the circulation, fivefold longer in hepatic tissue, and was more efficiently delivered to a variety of tissues. |
