N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents

Salvatore Nicoletti, Karin Seifert, Ian H. Gilbert (Lead / Corresponding author)

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    Abstract

    Leishmaniasis is a major health problem in many parts of the world, caused by various species of Leishmania. Amastigotes are the clinically relevant form of the parasite in the human host and reside in the parasitophorous vacuole within macrophages. Polymer-drug conjugates have been used for lysosomotropic drug delivery and have already shown potential in anticancer and antileishmanial chemotherapy. We synthesised N-(2-hydroxypropyl) methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates in which the AmB was attached to the polymer through a degradable GlyPheLeuGly linker. Antileishmanial activity was assessed in vitro against intracellular amastigotes in host macrophages [murine peritoneal exudate macrophages (PEMs), murine bone marrow-derived macrophages (BMMs) and differentiated THP-1 cells]. The most potent copolymers had 50% effective concentration (EC50) values of 0.03 mu g/mL AmB equivalent against Leishmania donovani amastigotes in PEMs and BMMs and an EC50 of 0.57 mu g/mL AmB equivalent against L. donovani in THP-1 cells. This activity was comparable with free AmB (EC50 = 0.03-0.07 mu g/mL against L. donovani in PEMs and BMMs and 0.24-0.42 mu g/mL against amastigotes in THP-1 cells) and Fungizone (R) (EC50 = 0.04-0.07 mu g/mL against amastigotes in PEMs). Conjugates also showed potent in vivo activity with ca. 50% inhibition of parasite burden at 1 mg/kg body weight. (C) 2008 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.

    Original languageEnglish
    Pages (from-to)441-448
    Number of pages8
    JournalInternational Journal of Antimicrobial Agents
    Volume33
    Issue number5
    DOIs
    Publication statusPublished - May 2009

    Keywords

    • Leishmaniasis
    • Copolymers
    • Amphotericin B
    • LIPOSOMAL AMPHOTERICIN-B
    • INDIAN VISCERAL LEISHMANIASIS
    • LIPID FORMULATIONS
    • DELIVERY
    • DRUGS
    • POPULATIONS
    • DIAGNOSIS
    • TOXICITY
    • DONOVANI
    • SINGLE

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