Covalent linkage of carboxypeptidase G2 to soluble dextrans--II. In vivo distribution and fate of conjugates.
The in vivo fate of the therapeutic enzyme, carboxypeptidase G2 (CPG2) in native form and covalently-linked to soluble dextrans was studied in the mouse using radiolabelled compounds. Clearance, from the blood, of all compounds tested was found to be as intact, active material, whilst excreted radiolabel was associated in all cases with low molecular weight substances. The clearance and excretion rates of native CPG2 were found to balance, but this was not so for dextran-CPG2 conjugate or CNBr-activated dextran. Tissue distribution studies demonstrated that there was little or no tissue uptake of native CPG2, whereas dextran-CPG2 conjugate, and CNBr-activated dextran were retained in the liver. Within the liver, the CPG2 component of dextran-CPG2 conjugate was degraded more rapidly than the dextran moiety. Blockade of reticulo-endothelial system (RES) led to increased half-lives of dextran CPG2 conjugate and CNBr-activated dextran, demonstrating the involvement of the RES in the clearance of these compounds. Impairment of RES activity did not affect the clearance rate of native CPG2. These results are discussed in relation to the potential use of dextran-CPG2 conjugates in cancer chemotherapy.
D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism*; D003488:Cyanogen Bromide / Q000494:pharmacology; D003911:Dextrans / Q000378:metabolism*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D014018:Tissue Distribution; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism*
D003911:Dextrans; D002268:Carboxypeptidases; D011623:gamma-Glutamyl Hydrolase; D003488:Cyanogen Bromide