Neoglycoproteins as carriers for receptor-mediated drug targeting in the treatment of experimental visceral leishmaniasis.
Methotrexate (MTX) coupled to mannosyl bovine serum albumin (BSA) was taken up efficiently through the mannosyl receptors present on macrophages. Binding experiments indicate that conjugation does not decrease the affinity of the neoglycoprotein for its cell surface receptor. The drug conjugate eliminated intracellular amastigotes of Leishmania donovani in mouse peritoneal macrophages about 100 times more efficiently than free drug on the basis of 50% inhibitory dose. Inhibitory effect of the conjugate was directly proportional to the density of sugar on the neoglycoprotein carrier. Colchicine and monensin, inhibitors of receptor-mediated endocytosis, can prevent the leishmanicidal effect of the conjugate. Antileishmanial effect of the conjugate can be competitively inhibited by mannose-BSA and mannan. In a murine model of experimental visceral leishmaniasis the drug conjugate reduced the spleen parasite burden by more than 85% in a 30-day model whereas the same concentration of free drug caused little effect. These results indicate that MTX-neoglycoprotein conjugate binds specifically to macrophages, and is internalized and degraded in lysosomes releasing the active drug to act on Leishmania parasites. These results also represent the potential for a general approach to intracellular targeting of clinical agents for macrophage-associated disorders.
Leishmania Group, Indian Institute of Chemical Biology, Calcutta.
P
P
Chakraborty
A N
AN
Bhaduri
P K
PK
Das
D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D037181:Lectins, C-Type; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008727:Methotrexate / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008985:Monensin / Q000494:pharmacology; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism*
D004337:Drug Carriers; D006023:Glycoproteins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D008985:Monensin; D003078:Colchicine; D008727:Methotrexate