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An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity
Published on: November 2, 2016
N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents
Salvatore Nicoletti1, Karin Seifert, Ian H Gilbert
1Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
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 (EC(50)) values of 0.03 microg/mL AmB equivalent against Leishmania donovani amastigotes in PEMs and BMMs and an EC(50) of 0.57 microg/mL AmB equivalent against L. donovani in THP-1 cells. This activity was comparable with free AmB (EC(50)=0.03-0.07 microg/mL against L. donovani in PEMs and BMMs and 0.24-0.42 microg/mL against amastigotes in THP-1 cells) and Fungizone (EC(50)=0.04-0.07 microg/mL against amastigotes in PEMs). Conjugates also showed potent in vivo activity with ca. 50% inhibition of parasite burden at 1mg/kg body weight.
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