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 leishmaniasis. Conjugation of doxorubicin did not decrease the affinity of the neoglycoprotein for the macrophage mannose receptor. Conjugated doxorubicin eliminated intracellular amastigotes of Leishmania donovani in peritoneal macrophages almost 12.5 times more efficiently than did the free drug and greatly reduced and possibly eliminated splenic intracellular parasites in four consecutive dosages at 5 micrograms/kg/day for 45 days. Free drug at a similar dose had little effect. The leishmanicidal effect of doxorubicin conjugate can be prevented by competitive inhibitors such as man-HSA or mannan and inhibitors of receptor-mediated endocytosis such as colchicine and monensin. These results not only indicate the potential of doxorubicin as an effective chemotherapeutic agent for leishmaniasis but also establish the use of mannosylated neoglycoprotein as a drug carrier in the therapy of macrophage-associated diseases.
Sett
R
R
Department of Molecular Cell Biology, Indian Institute of Chemical Biology, Calcutta.
Sarkar
K
K
Das
P K
PK
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity*; D004337:Drug Carriers; D006023:Glycoproteins; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000469:parasitology / Q000502:physiology*; D008358:Mannose; D051379:Mice; D012709:Serum Albumin
D004337:Drug Carriers; D006023:Glycoproteins; D012709:Serum Albumin; C023840:mannose-bovine serum albumin conjugate; D004317:Doxorubicin; D008358:Mannose