MACROPHAGE-DIRECTED DELIVERY OF DOXORUBICIN CONJUGATED TO NEOGLYCOPROTEIN USING LEISHMANIASIS AS THE MODEL DISEASE

The antileishmanial potency of doxorubicin conjugated to mannose-human serum albumin (man-HSA) was tested in experimental visceral leishmani asis. Conjugation of doxorubicin did not decrease the affinity of the neoglycoprotein for the macrophage mannose receptor. Conjugated doxoru bicin eliminated intracellular amastigotes of Leishmania donovani in p eritoneal macrophages almost 12.5 times more efficiently than did the free drug and greatly reduced and possibly eliminated splenic intracel lular parasites in four consecutive dosages at 5 mug/kg/day for 45 day s. Free drug at a similar dose had little effect. The leishmanicidal e ffect of doxorubicin conjugate can be prevented by competitive inhibit ors such as man-HSA or mannan and inhibitors of receptor-mediated endo cytosis such as colchicine and monensin. These results not only indica te the potential of doxorubicin as an effective chemotherapeutic agent for leishmaniasis but also establish the use of mannosylated neoglyco protein as a drug carrier in the therapy of macrophage-associated dise ases.