Methotrexate conjugate with branched polypeptide influences Leishmania donovani infection in vitro and in experimental animals

György Kóczán, Asoke C. Ghose, Ananda Mookerjee, Ferenc Hudecz

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Methotrexate (MTX) has been coupled to various structurally related, polycationic (poly[Lys(DL-Alam)] (AK), poly[Lys(Seri-DL-Alam)] (SAK), poly[Lys(DL-Alam-Leui)] (ALK)), or amphoteric (poly[Lys(Glui-DLAlam)] (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.

Original languageEnglish
Pages (from-to)518-524
Number of pages7
JournalBioconjugate Chemistry
Volume13
Issue number3
DOIs
Publication statusPublished - May 30 2002

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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