Methotrexate (MTX) has been coupled to various structurally related, polycationic (poly[Lys(DL-Ala m )] (AK), poly[Lys(Ser i -DL-Ala m )] (SAK), poly[Lys(DL-Ala m -Leu i )] (ALK)), or amphoteric (poly[Lys(Glu i -DLAla m )] (EAK)) synthetic branched polypeptides containing poly [L-Lys] backbone by the aid of BOP reagent. The average degree of MTX incorporation was found to be dependent on the charge properties of the polymer. Under the experimental conditions used, the molar substitution ratio achieved was higher for polycations (25%) than for the amphoteric polypeptide (10%). We have studied the effect of polycationic polypeptides on Leishmania donovani infection. Results demonstrated that MTX conjugates in which the drug is covalently attached to carrier have pronounced leishmanicid activity. In this communication we showed that (a) a branched polypeptide-methotrexate conjugate with a polycationic carrier (ALK) increases the effect of MTX against Leishmania donovani infection in mice; (b) the covalent bond between the carrier and methotrexate is essential for both in vivo and in vitro activity; and (c) the number of Leishmania donovani parasites in infected macrophages are markedly reduced in conjugate treated animals. In vitro observation might also indicate that the MTX conjugate exhibits an effect through an uptake by macrophages which is different from that of the free drug. INTRODUCTONMethotrexate (MTX, 1 L-4-amino-N 10 -methylpteroylglutamic acid), a folate antimetabolite, has been in clinical use for more than 35 years. It is a potent anticancer agent of proven benefit in the treatment of acute leukemia, osteogenic sarcoma (1), and of rheumatological disorders (2-4). Recently its inhibitory potential has been demonstrated against a group of intracellular parasites (Leishmania) of macrophages (5). Visceral leishmaniasis or kala-azar in man is caused by the protozoan parasite Leishmania donovani, which proliferates intracellularly within the mononuclear phagocytes of the infected host (6).Methotrexate has been linked to various macromolecules such as BSA, mannosylated-, galactosylated-, or glucosylated-BSA (7, 8), mannosylated-HSA (9), or maleylated-BSA (10), for delivery into cells containing L. donovani parasites or to polylysine for studying the mechanism of action of cellular uptake by pinocytosis in mice and human tumor cell lines (11)(12)(13)(14).The methods of conjugation of methotrexate to these carriers have involved predominantly the glutamic acid moiety. Activation of R-and γ-carboxyl groups has been achieved in situ in the presence of the carrier using water soluble carbodiimide like EDC (15) or by ester formation with N-hydroxysuccinimide (11). (None of the above methods reported have been used for selective derivatization of R-or γ-carboxyl groups of MTX (15).)MTX was also one of the first antitumor drug attached covalently to high molecular weight carriers to improve the therapeutic index by site-specific targeting and/or by changing the pharmacological properties of MTX to provide controlle...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.