ANTAGONISTS OF THE MANNOSE RECEPTOR AND THE LDL RECEPTOR-RELATED PROTEIN DRAMATICALLY DELAY THE CLEARANCE OF TISSUE-PLASMINOGEN ACTIVATOR

Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose recepto r on endothelial liver cells and the LDL receptor-related protein (LRP ) on parenchymal liver cells were reported to contribute to liver upta ke. Methods and Results In this study, we addressed whether TPA cleara nce can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster mannosides was synthesized, and their affinity fo r the mannose receptor was determined. A cluster mannoside carrying si x mannose groups (M(6)L(5)) displayed a subnanomolar affinity for the mannose receptor (K-i=0.41+/-0.09 nmol/L). Preinjection of M(6)L(5) (1 .2 mg/kg) reduced the clearance of I-125-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M(6)L(5), combined with its accessible synthesis and high specifici ty for the mannose receptor, makes it a promising agent to improve the pharmacokinetics of TPA. Blockade of LRP by 39-kD receptor-associated protein (GST-RAP) also inhibited TPA clearance by 60%. Finally, combi ned preinjection of M(6)L(5) and GST-RAP almost completely abolished r educed liver uptake of TPA and delayed its clearance by a factor of 10 . Conclusions It can be concluded that (1) the mannose receptor and LR P appear to be the sole major receptors responsible for TPA clearance and (2) therapeutic levels of TPA can be maintained for a prolonged ti me span by coadministration of the aforementioned receptor antagonists .